Depression Esketamine Ketamine

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NOVA Health Recovery | Alexandria, Va 22306 | Call for esketamine and nasal ketamine as well as IV Ketamine for depression, PTSD, anxiety  703-844-0184 < Link

Call NOVA Health Recovery at 703-844-0184 for a free consultation for a Ketamine infusion. No referral needed. We offer intranasal Ketamine follow up therapy as well. Alexandria, Va 22306.

Call NOVA Health Recovery at 703-844-0184 for a free consultation for a Ketamine infusion. No referral needed. We offer intranasal Ketamine follow up therapy as well. Alexandria, Va 22306.

From Popular Anesthetic to Antidepressant, Ketamine Isn’t the Drug You Think It Is

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.

Depression Esketamine Ketamine OCD

KETAMINE CENTER NORTHERN VIRGINIA | 703-844-0184 | NOVA HEALTH RECOVERY | SPRAVATO KETAMINE NASAL SPRAY CENTER |ALEXANDRIA, VA 22306 | KETAMINE FOR DEPRESSION AND PTSD | 22304 |20176 | 703-844-0184 | 22101 | 22102 | FAIRFAX KETAMINE INFUSION CENTER 22304 | DR. SENDI | Ketamine and OCD, PTSD, Depression, Anxiety

Call NOVA Health Recovery at 703-844-0184 for a free consultation for a Ketamine infusion. No referral needed. We offer intranasal Ketamine follow up therapy as well. Alexandria, Va 22306.

Call NOVA Health Recovery at 703-844-0184 for a free consultation for a Ketamine infusion. No referral needed. We offer intranasal Ketamine follow up therapy as well. Alexandria, Va 22306.

Ketamine: A Promising Novel Therapy for Anxiety and PTSD

Ketamine was originally approved by the US Food and Drug Administration (FDA) as an anesthetic, but is increasingly being used to treat mood disorders, such as treatment-resistant depression, anxiety disorders, and post-traumatic stress disorder (PTSD).1,2 Several studies have also found it to be effective for treating suicidal ideation.3,4

“Ketamine can play an important role in the treatment of anxiety disorders,” according to Prakash Masand, MD, co-founder, chairman, and CEO of Centers of Psychiatric Excellence (COPE) (https://www.copepsychiatry.com) and adjunct professor at the Academic Medicine Education Institute, Duke-National University of Singapore Medical School (Duke-NUS).

“Nowadays, people with anxiety disorders are treated either with a generic antidepressant, such as an SSRI (selective serotonin reuptake inhibitor), an SNRI (selective norepinephrine reuptake inhibitor), or a benzodiazepine and if they don’t respond to one of these, they get a trial of another or several more,” Dr Masand said.

However, between 30% and 40% of these patients will not achieve remission, despite 3 or 4 different traditional agents, and even with evidence-based nonpharmacologic therapies, such as cognitive behavioral therapy (CBT) or mentalization-based therapy (MBT), he noted.

“No good current strategies are available for these non-responders, so novel agents are being studied — including ketamine, which is accumulating an evidence base as [being] rapidly effective for an array of anxiety disorders, including social anxiety disorder (SAD) and PTSD,” he said.

How Does Ketamine Work?

A growing body of evidence points to the role of glutamate, a widely distributed excitatory neurotransmitter, in mediating response to stress and the formation of traumatic memories.2 Ketamine is an ionotropic glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist. Its antidepressant and anti-anxiety effects are presumed to occur through activating synaptic plasticity by increasing brain-derived neutrophic factor translation and secretion and also by inhibiting glycogen synthase kinase-3 and activating mammalian target of rapamycin signaling.5

Brain-derived neutrophic factor plays a role in behavioral responses to classical antidepressants, but the impact on synaptic plasticity may take several weeks to manifest. In contrast, ketamine-mediated synaptic plasticity changes appear to occur within a matter of hours after ketamine administration.5

“The current thinking is that eventually, 6 to 12 weeks after initiating treatment with traditional antidepressants, dendritic growth and increased synaptic connections occur but with ketamine, these can occur within 24 hours of the infusion,” Dr Masand said.

Ketamine and Anxiety: An Increasing Evidence Base

“Ketamine has been studied and shown [to be] effective with an array of anxiety disorders, including SAD, general anxiety disorder (GAD), and PTSD, although the data on its effectiveness in obsessive compulsive disorder (OCD) are more mixed,” Dr Masand observed.

GAD/SAD

  • A small study of patients with GAD and/or SAD (n=12) compared 3 ascending ketamine doses to midazolam. Each was given at 1-week intervals, with midazolam counterbalanced in dosing position across patients. Ketamine was found to dose-dependently improve scores on the Fear Questionnaire. Moreover, it’s impact on decreasing theta frequency in the right frontal sites assessed via  electroencelphalogram (EEG) was comparable to that of conventional anxiolytics.6
  • Glue et al evaluated the efficacy and safety of ketamine in 12 patients with refractory GAD and/or SAD who were not currently depressed using an ascending single-dose at weekly intervals study design. Within 1 hour of dosing, patients reported reduced anxiety, which persisted for up to 7 days.7
  • A continuation of that study evaluated the impact of maintenance treatment ketamine in patients with GAD and/or SAD (n=20) and found that 18 of the 20 patients reported ongoing improvements in social functioning and/or work functioning during maintenance treatment. The researchers concluded that maintenance therapy ”may be a therapeutic alternative for patients with treatment-refractory GAD/SAD.”8

“What is interesting about this study is that the impact of just one infusion lasted for 14 weeks, suggesting that patient[s] with anxiety disorders might have longer maintenance of response than patients with major depression, where the response has been maintained for only one week,” Dr Masand commented.

Anxious Depression

  • A study of patients with anxious and non-anxious bipolar depression (n=21 for both groups) found that both anxious and non-anxious patients with bipolar depression had significant antidepressant responses to ketamine, although the anxious depressed group did not show a clear antidepressant response disadvantage over the non-anxious group.9 “Given that anxiety has been shown to be a predictor of poor treatment response in bipolar depression when traditional treatments are used, our findings suggest the need for further investigations into ketamine’s novel role in the treatment of anxious bipolar depression.,” the investigators concluded.9

Related Articles

OCD

  • An open-label trial of ketamine in 10 patients with treatment-refractory OCD found that ketamine’s effects on OCD symptoms, in contrast to depressive symptoms, did not seem to persist or progress after the acute effects of ketamine had dissipated.10
  • On the other hand, another randomized controlled trial (RCT) of 15 patients with OCD found that anti-OCD effects from a single intravenous dose of ketamine persisted for more than 1 week in some patients with OCD with constant intrusive thoughts, demonstrating that “a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an [SSRI].”11

PTSD

In PTSD, there is “mounting evidence for a role of the excitatory neurotransmitter glutamate in stress responsiveness, the formation of traumatic memories, and the pathophysiology of PTSD, raising the possibility of identifying novel glutamatergic interventions for this disorder.”12

  • One double-blind study demonstrated that infusion of ketamine rapidly and significantly reduces symptom severity in patients with  PTSD compared with midazolam.2
  • Another study found that administration of ketamine immediately after witnessing a traumatic event has been shown to prevent the enhancement of passive avoidance learning in mice.13Ketamine may thus target the mechanisms involved in the consolidation of traumatic memory and may enable the brain to reconsolidate memory and release trauma.14
  • A case study of a child with PTSD reported remission from behavioral dysregulation after receiving procedural ketamine.15

Drawbacks and Potential Adverse Effects

The main concern regarding the use of ketamine for anxiety disorders is the lack of a road map regarding maintenance, Dr Masand noted.

“At COPE, we have found that roughly 30% to 40% of our patients being treated with ketamine require maintenance infusions, and we highly personalize this approach so that patients can identify early signs of recurrence or relapse and we can devise a treatment schedule to prevent them,” he said.

Some patients continue treatment with pharmacotherapy, including standard antidepressants, benzodiazepines, or a mood stabilizer such as valproate and some patients become more receptive to psychotherapies such as CBT,” he stated.

However, “there is very little data regarding what happens long-term in this patient population.”

“Most side effects are mild and transient,” Dr Masand reported. “Patients must be monitored because of potential increases in blood pressure and pulse.”

Additional adverse events include nausea or vomiting, which are also mild and transient. Patients may be pre-treated with prophylactic anti-nausea medication, such as ondansetron, to pre-empt these symptoms, he said.

Some patients experience dissociation, or an out-of-body experience, which is also usually transient but seen by some patients as “annoying,” he noted. “Dissociative experiences are sometimes seen as a biomarker for insufficient response and suggest that the dose should be increased.”

Providers should be aware that cystitis and lower urinary tract pathologies (eg, detrusor over-activity) have been reported in long-term ketamine users, but typically only at high doses.16

Ketamine’s psychedelic effects make it a” popular recreational drug.”16 At lower doses, the predominant effects are stimulating, and users experience mild dissociation with hallucinations and a distortion of time and space. However, higher doses can induce more severe, schizophrenia-like symptoms and perceptions.16 Although these effects resolve rapidly, long-term use “can cause more pronounced and persistent neuropsychiatric symptoms. For this reason, ketamine should be “used cautiously with other drugs that alter mood and perception, including alcohol, opioids, benzodiazepines and cannabis.”16

Promising Role

“Ketamine for treatment-resistant depression has a robust evidence base and a rapidly-growing evidence base for its use in anxiety disorders,” Dr Masand said.

“Given the gaps in current treatment, this promising agent is occupying a more promising role in treatment of anxiety disorders, such as PTSD. Considering how common PTSD is, ketamine can make an important difference for a large number of people who suffer from this debilitating condition,” he concluded.

First Person Account of Ketamine Therapy: An Interview with Kimberly Palmer

To gain insight into the experience of ketamine treatment in a person with depression and anxiety, Psychiatry Advisor interviewed Kimberly Palmer of Los Angeles, California. Ms Palmer received treatment at the Ketamine Clinics of Los Angeles (https://www.ketamineclinics.com). Ms Palmer works as a program manager for a consulting company where she organizes and runs corporate events for small groups.

Psychiatry Advisor: What made you decide to pursue ketamine treatment?

Ms Palmer: I was raised in an abusive home, and as an adult I had severe major depression, as well as anxiety. I was treated with medications, such as antidepressants, but they had many adverse events and they ended up making me feel like a zombie, so I discontinued them. I managed okay for a while, but then I had another major depressive episode.

I was receiving psychotherapy at the time and it was only moderately helpful — not enough to stop the episode. Fortunately, I knew someone who works at a ketamine clinic. She told me how many patients had been helped by ketamine and I was interested, mostly because the adverse events of ketamine seemed mild and are not long-term.

Psychiatry Advisor: What were your experiences during your infusion?

Ms Palmer: I felt incredible during the infusion. The best way I can describe it is by referring to the movie Avatar, specifically the scene in which the protagonist is walking through a jungle at night for the first time and touching all the plants, which light up with pretty colors—very vivid, colorful, and not linear. There was the sensation of being on a sort of roller coaster, riding through different scenes.

At one point, it felt as though my chair was on a cloud. Then suddenly, the chair disappeared and I was floating on the cloud. It was a wonderful experience.

Psychiatry Advisor: How did the ketamine treatment affect you afterwards?

Ms Palmer: After only one treatment, it was as if a switch had flipped in my brain that allowed me to digest things and move beyond my trauma. Before the infusion, a lot of what was going on with me had to do with self-esteem issues and negative self-talk. These were behaviors learned over many years. After the infusion, the negative self-talk immediately disappeared. All of those thoughts — such as telling myself I am not good enough — that were preventing me from working through emotional issues, were resolved. I was able to start looking at things more objectively rather than taking them personally, and not take on responsibility for other people’s emotions and reactions.

I am currently working with a therapist and a life coach to help me feel more comfortable with communication because I was raised not to ask for things and to put up with anything I’m asked to do. As a result, I have developed a much more positive outlook of myself and the world.

Psychiatry Advisor: How many ketamine treatments have you had?

Ms Palmer: Over a 6-month period I had 6 treatments, which were all very helpful. Then, 6 months after the conclusion of this first series of treatments, some new issues came up, so I received 2 more — one regular 60-minute treatment and one extended 90-minute treatment.

Recently, with the holidays coming up, I decided to pre-empt the effect of some stressors and have another treatment. My most recent infusion took place the day after my father passed away. I noticed that during the infusion, I was able to steer myself away from negative thoughts about that issue. Although I cannot control what visions or experiences I might have, I do have some control over the direction of my thoughts and the after-effects have been positive and helpful.

Psychiatry Advisor: Did you have any adverse events from the treatments?

Ms Palmer: I had no negative physical effects. I had one mild bad reaction, when I came to the treatment session in an agitated state because I had gotten into a fight with someone right before. I was sad and crying  by the time I finished the infusion. But I was in a bad headspace before I even walked into the room. And my experience was not scary, only sad.

Psychiatry Advisor: What impact has your treatment had on your day-to-day life?

Ms Palmer: My depression had interrupted my schooling. I was in school for 3 and a half years and then I hit a roadblock. After the treatments, I was able to complete my studies and graduated with a BA in business administration and management.

My job is stressful. I counterbalance the stress with hobbies like surfing and photography. But there are still stressors, and I have a dog who is reaching the end of life, which is affecting me. The ketamine treatments have helped me to manage those stressors. 

References

  1. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disordersJAMA Psychiatry. 2017;74(4):399-405.
  2. Feder A, Parides M, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trialJAMA Psychiatry. 2014;71(6):681-688.
  3. Murrough JW, Soleimani L, DeWilde KE, et al. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trialPsychol Med. 2015;45(16):3571-3580.
  4. Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysisAm J Psychiatry. 2018;175(2):150-158.
  5. Schwartz J, Murrough JW, Iosifescu DV. Ketamine for treatment-resistant depression: recent developments and clinical applicationsEvid Based Ment Health. 2016;19(2):35-38.
  6. Shadli SM, Kawe T, Martin D, McNaughton N, Neehoff S, Glue P. Ketamine effects on EEG during therapy of treatment-resistant generalized anxiety and social anxiety [published online April 24,2018]. Int J Neuropsychopharmacology. doi:10.1093/ijnp/pyy032
  7. Glue P, Medlicott NJ, Harland S, et al. Ketamine’s dose-related effects on anxiety symptoms in patients with treatment refractory anxiety disorders. J Psychopharmacol. 2017;31(10):1302-1305.
  8. Glue P, Neehoff SM, Medlicott NJ, Gray A, Kibby G, McNaughton N. Safety and efficacy of maintenance ketamine treatment in patients with treatment-refractory generalised anxiety and social anxiety disordersJ Psychopharmacol. 2018;32(6):663-667.
  9. Ionescu DF, Luckenbaugh DA, Niciu MJ, Richards EM, Zarate CA. A single infusion of ketamine improves depression scores in patients with anxious bipolar depressionBipolar Disord. 2014;17(4):438-443.
  10. Bloch MH, Wasylink S, Landeros-Weisenberger A, et al. Effects of ketamine in treatment-refractory obsessive-compulsive disorderBiol Psychiatry. 2012;72(11):964-970.
  11. Rodriguez CI, Kegeles LS, Levinson A, et al. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology. 2013;38(12):2475-2483.
  12. Girgenti MJ, Ghosal S, LoPresto D, Taylor JR, Duman RS. Ketamine accelerates fear extinction via mTORC1 signalingNeurobiol Dis. 2016;100:1-8.
  13. Ito W, Erisir A, Morozov AObservation of distressed conspecific as a model of emotional trauma generates silent synapses in the prefrontal-amygdala pathway and enhances fear learning, but ketamine abolishes those effects. Neuropsychopharmacology. 2015; 40(11):2536-2545.
  14. Fattore L, Piva A, Zanda MT, Fumagalli G, Chiamulera C. Psychedelics and reconsolidation of traumatic and appetitive maladaptive memories: focus on cannabinoids and ketaminePsychopharmacology (Berl). 2018;235(2):433-445.
  15. Donoghue AC, Roback MG, Cullen KR. Remission from behavioral dysregulation in a child with PTSD after receiving procedural ketaminePediatrics. 2015;136(3):e694-e696.
  16. Li L, Vlisides PE. Ketamine: 50 years of modulating the mindFront Hum Neurosci. 2016;10:612.

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Depression Esketamine

Ketamine Center Northern Virginia | 703-844-0184 | NOVA Health Recovery | Spravato Ketamine nasal spray Center |Alexandria, Va 22306 | Ketamine for depression and PTSD | 22304 |20176 | 703-844-0184 | 22101

Call NOVA Health Recovery at 703-844-0184 for a free consultation for a Ketamine infusion. No referral needed. We offer intranasal Ketamine follow up therapy as well. Alexandria, Va 22306.

Call NOVA Health Recovery at 703-844-0184 for a free consultation for a Ketamine infusion. No referral needed. We offer intranasal Ketamine follow up therapy as well. Alexandria, Va 22306.

VA to offer new ketamine-based nasal spray to help combat depression

The newest FDA-approved medication to treat severe depression, a nasal spray based on the anesthetic (and misused hallucinogenic party drug) ketamine, will soon be available to veterans treated within the Department of Veterans Affairs.

In a move that may help thousands of former service members with depression that has not improved with other treatments, VA officials announced Tuesday that the department’s doctors are now authorized to prescribe Spravato, the brand name for esketamine, a molecular variation of ketamine.

The decision to offer a drug hailed by many as a breakthrough in treatment for its speedy results — often relieving symptoms in hours and days, not weeks — shows the VA’s “commitment to seek new ways to provide the best health care available for our nation’s veterans,” Secretary Robert Wilkie said in a release.

“We’re pleased to be able to expand options for Veterans with depression who have not responded to other treatments,” Wilkie added.

The treatment will be available to veterans based on a physician’s assessment and only will be administered to patients who have tried at least two antidepressant medications and continue to have symptoms of major depressive disorder.

An estimated 16 million Americans have had at least one major episode of depression, and of those, 1 in 3 are considered treatment-resistant. In the veteran population of 20 million, the estimated diagnosis rate of depression is 14 percent — up to 2.8 million veterans. Between one-third and half of those veterans may be treatment-resistant.

The lack of effective medications for difficult-to-treat patients prompted the Food and Drug Administration to place esketamine on a fast track, expediting its review of the drug to ensure that it went to patent as soon as safely possible, according to administration officials.

“Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process, including a robust discussion with our external advisory committees, were important in our decision to approve this treatment,” said Dr. Tiffany Farchione, acting director of the FDA’s Center for Drug Evaluation and Research Division of Psychiatry Products, in a release.

As with any other medication, there are risks. Spravato carries a boxed warning for side effects that include misuse, the reason it is administered under a doctor’s supervision. The list of side effects includes sedation and blood pressure spikes and disassociation, such as feelings of physical paralysis and out-of-body experiences. It also can cause suicidal thoughts and behaviors.

Acknowledging the dangers, FDA made esketamine available only through a restricted distribution system.

A veteran prescribed Spravato would inhale the nasal spray at a medical facility while under supervision of a medical provider, and would be monitored for at least two hours after receiving the dose. A typical prescription includes twice-weekly doses the first month, followed by a single dose weekly or biweekly as needed. Spravato cannot be dispensed for home use.

Spravato is made by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. It is the first major antidepressant medication to hit the market in 30 years.

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The FDA Approved a Ketamine-Like Nasal Spray for Hard-to-Treat Depression

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Treatment-resistant depression affects 1 in 3 of the estimated 16.2 million adults in the US who have suffered at least one major depressive episode. For them, two or more therapies have failed and the risk of suicide is much greater. It’s a grim prognosis.

There are few therapies for depression that resists treatment, which is why the FDA granted this new drug application Fast Track and Breakthrough Therapy status. On March 5, the Food and Drug Administration approved a new treatment called Spravato, which is an esketamine nasal spray.

On February 12, 2019, I participated in the FDA review of this drug. Practically speaking, esketamine is essentially the same as ketamine, which is a painkillerwith hallucinogenic effects and used illegally. As a member of the Drug Safety and Risk Management Advisory Committee of the FDA, I voted with the majority of that panel 14-2, to approve esketamine only for people who have treatment-resistant depression.

For more than 20 years, I have researched illegal drug use and addiction. As a medical anthropologist, my work is oriented to understanding the perspectives and behaviors of people actively using illegal drugs. My research often involves fieldwork, which means participating in the lives of people as they go about their everyday routines. This has given me a personalized and practical outlook on illegal drug use. Many of the people I currently interview are heroin injectors who first started opioid use by misusing prescription drugs.

Ketamine is not a street drug

But many drugs, especially those for the treatment of mental illness, have powerful effects on the central nervous system. How the drug is distributed and administered must minimize risk. What if the drug is addicting?

Some reports about esketamine have sensationalized this issue by referring to ketamine as a highly addictive street drug. In my research, this is not true. First, ketamine use is rare. The last time I interviewed a ketamine users was nearly 20 years ago and, since its introduction in 1964, there have been no significant trends or outbreaks in its diversion or use.

Not all illegal drugs are sold “on the street.” Street drugs are staples of the illegal drug economy, which is run by drug trafficking organizations. Prescription opioids, heroin, cocaine, and marijuana are street drugs sold in open-air drug markets, where such markets exist. Hallucinogens and exotic, designer, and other less popular drugs are rarely available in these settings. They simply do no appeal to enough users to make them profitable for drug traffickers to supply. Ketamine has always been in this second group.

Are ketamine or esketamine addictive?

Ketamine is short-acting—between two and four hours—and produces euphoria, sustained pain relief, and sedation mixed with powerful hallucinogenic effects. Taking this drug can be very unpleasant. Out-of-body experiences, time perception distortions, tunnel vision. and dissociation are common. These effects limit the popularity of ketamine and make it difficult to use habitually. A person can take heroin everyday and function. Ketamine is disruptive.

Another reason that ketamine isn’t popular on the street is that users do not have to keep using it to avoid withdrawal. There is no withdrawal syndrome associated with ketamine; when people stop using it, they do not get sick. This is actually a benefit, because fear of withdrawal is often a major motivation for the continuation of drug use. Unlike street drugs, its appeal is limited and its addiction liability is comparatively low.


On balance, the profile of ketamine is more like LSD than cocaine or opioids. People do not get addicted. This does not mean that ketamine or esketamine is safe. Its access should be restricted and use monitored by a physician.

How will people take esketamine for depression?

The manufacturer is placing important restrictions on the drug. It will not be available at local pharmacies and never for take-home use. A person receiving the treatment, which was developed by Johnson & Johnson and delivered as a nasal spray, will be under observation and care of a health professional trained in the therapy. The drug will be given in an office or approved health center, and the patient will not be allowed to drive until the day after treatment. The patient will also need to take an oral antidepressant, the FDA says.

Given its effectiveness and the proposed risk evaluation and mitigation strategy, the benefits outweigh the risks of esketamine for the treatment of depression that has not responded to other treatments. Like any new treatment, as manufacturers make this product available, monitoring it will be important to make sure the benefits outweigh the costs. People living with the misery of treatment-resistant depression need more options, and this drug should help.

Lee Hoffer is a medical anthropologist at Case Western Reserve University who studies substance use disorder and the use of illicit drugs. He was a member of the FDA advisory committee that recommended last month that the esketamine be approved for treatment-resistant depression.

MONITORING THE FUTURE drug trends Link

National Survey on Drug Use and Health




Depression Esketamine Ketamine

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Fast-Acting Depression Drug, Newly Approved, Could Help Millions

A nasal spray version of the drug ketamine has shown promise as an antidepressant, even if its properties still aren’t well understood.

Of the 16 million American adults who live with depression, as many as one-quarter gain little or no benefit from available treatments, whether drugs or talk therapy. They represent perhaps the greatest unmet need in psychiatry. On Tuesday, the Food and Drug Administration approved a prescription treatment intended to help them, a fast-acting drug derived from an old and widely used anesthetic, ketamine.

The move heralds a shift from the Prozac era of antidepressant drugs. The newly approved treatment, called esketamine, is a nasal spray developed by Janssen Pharmaceuticals Inc., a branch of Johnson & Johnson, that will be marketed under the name Spravato. It contains an active portion of the ketamine molecule, whose antidepressant properties are not well understood yet.

“Thank goodness we now have something with a different mechanism of action than previous antidepressants,” said Dr. Erick Turner, a former F.D.A. reviewer and an associate professor of psychiatry at Oregon Health & Science University. “But I’m skeptical of the hype, because in this world it’s like Lucy holding the football for Charlie Brown: Each time we get our hopes up, the football gets pulled away.”

The generic anesthetic is already increasingly available for depression, at hundreds of clinics around the country that provide a course of intravenous treatments, and studies suggest it can help treatment-resistant people. It often causes out-of-body and hallucinogenic sensations when administered; in the 1980s and 1990s it was popular as a club drug, Special K.

The cost for these treatments typically is out of pocket, as the generic anesthetic is not approved by the F.D.A. for depression. In contrast, esketamine likely would be covered under many insurance plans, and its side effects, though similar to those of generic ketamine, are thought to be less dramatic.

The recommended course of the newly approved drug is twice a week, for four weeks, with boosters as needed, along with one of the commonly used oral antidepressants. F.D.A. approval requires that doses be taken in a doctor’s office or clinic, with patients monitored for at least two hours, and their experience entered in a registry; patients should not drive on the day of treatment.

Esketamine, like ketamine, has the potential for abuse, and both drugs can induce psychotic episodes in people who are at high risk for them. The safety monitoring will require doctors to find space for treated patients, which could present a logistical challenge, some psychiatrists said.

The cost for a one-month course of treatment will be between $4,720 and $6,785, said Janssen, and experts said it will give the company a foothold in the $12 billion global antidepressant market, where most drugs now are generic.[L

The approval of esketamine marks a new approach to treating serious mood problems, experts said. Prozac and similar drugs enhance the activity of brain messengers such as serotonin; they are mildly effective, but they take weeks or months for their effects to be felt, and for many patients they provide little or no relief from depression. In contrast, the ketamine-based compounds — several others are being developed — work within hours or days, and are effective in some people who are considered “treatment resistant,” meaning they have not benefited from other antidepressants.

“These are exciting times, for sure,” said Dr. Todd Gould, an associate professor of psychiatry in the University of Maryland School of Medicine. “We have drugs that work rapidly to treat a very severe illness.” Dr. Gould was not involved in the Janssen study but has identified a metabolite, or ketamine breakdown product, that could be developed into another drug.

Experts with long experience in treating depression were encouraged by the news, but also chary. The effectiveness of the previous class of antidepressants such as Prozac and Paxil was vastly exaggerated when they came on the market. And the results of esketamine trials, which were paid for and carried out by Janssen, were mixed.

In each trial submitted, all patients were started on a new antidepressant drug, and given a course of esketamine treatment or a placebo. In one monthlong study, those on esketamine performed better statistically than those on placebo, reducing scores on a standard, 60-point depression scale by 21 points, compared to 17 points for placebo. But in two others trials, the drug did not statistically outperform placebo treatment. Historically, the F.D.A. has required that a drug succeed in two short-term trials before it is approved; the agency loosened its criteria for esketamine, opting instead to study relapse in people who did well on the drug.

In that trial, Janssen reported that only about one-quarter of subjects relapsed, compared to 45 percent of subjects who received the placebo spray. All the subjects had been given a diagnosis of treatment-resistant depression, or T.R.D., having previously failed multiple courses of drug treatment.

“We’ve had nothing new in 30 years,” said Steven Hollon, a professor of psychiatry and behavior sciences at Vanderbilt University. “So if this drug is an effective way to get a more rapid response in people who are treatment resistant, and we can use it safely, then it could be a godsend.”

One question that will need to be answered is how well esketamine performs in comparison to intravenous ketamine.

Theresa, 57, an adjunct professor of English in New York, who asked that her last name be omitted to protect her privacy, has lived much of her life with deep depression. She tried a course of I.V. generic ketamine last summer, at a local clinic, which typically entails a half-dozen infusions, given over a couple of weeks, for about $500 apiece, with follow-up “booster” treatments as needed.

“I remember floating, I was really high,” she said. “I was tripping on sounds, textures and shapes, that was very much a part of it.”

The first infusion provided no relief, she said. But after the third or fourth, she noticed a satisfying “shift” in her underlying mood. “It’s a hard thing to describe. I was still anxious, but I felt somehow more solid, like something gelled within me, and my husband has noticed it, too.”

Dr. Glen Brooks, the founder and medical director of NY Ketamine Infusions, a clinic in downtown Manhattan, said he has treated some 2,300 people, of all ages, with intravenous ketamine, the generic anesthetic. His clients had received a variety of diagnoses, including post-traumatic stress, anxiety, and obsessive-compulsive disorder, as well as depression.

“What they all have in common is that other medications have failed,” Dr. Brooks, an anesthesiologist, said. “They’re hopeless, and they think, ‘Nothing else has worked, why should this?’” He said that, in his experience, the infusions quickly reduced symptoms for teenagers and young adults, but seemed to be less effective for people over 50.

The data that Janssen presented to the F.D.A. likewise suggested that esketamine was less effective in people aged 65 and older, barely better than placebo treatment.

Ketamine was developed more than five decades ago as a safer alternative to the anesthetic phencyclidine, or PCP, and is used worldwide, in operating rooms, on the battlefield and in pediatric clinics. The World Health Organization has listed ketamine as one of its essential medicines since 1985.

By the 1990s, interest turned to the drug’s potential to combat depression, when a government scientist named Phil Skolnick argued that targeting glutamate pathways — the primary “excitatory,” or neuroactivating, brain processes — could produce antidepressant effects. In 2000, a team of researchers at Yale University and the Connecticut Mental Health Center, led by Dr. Robert M. Berman, reported that doses of ketamine provided quick relief to seven people with depression.

The field took off in 2006, when a team at the National Institute of Mental Health led by Dr. Carlos Zarate Jr. reported that 18 treatment-resistant people who received the drug intravenously reported that their despair lifted within hours.

“What seems remarkable is that the drug also seems to help domains other than depression, like anxiety, suicidal thinking, and anhedonia” — the inability to feel pleasure — said Dr. Zarate, chief of the N.I.M.H.’s experimental therapeutics and pathophysiology branch. “It seems to have more broad effects, on many areas of mood.”

The apparent ability of ketamine to blunt suicidal thinking is particularly compelling, and Janssen is pursuing this indication for esketamine. In jails and psychiatry wards, suicide is an acute risk for people in crisis, and a fast-acting drug could save many lives, doctors said.

For now, no one knows whether esketamine, or any of the other ketamine-based compounds being studied, are any more effective than the generic anesthetic itself — or, for that matter, whether the out-of-body and hallucinatory “side effects” are in fact integral to its antidepressant properties.

“For that, we will need head-to-head studies,” Dr. Zarate said. “And we don’t have those yet.”





Depression Esketamine Ketamine

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For a conclusion of this study – the current experiments demonstrate that PNNs, the specialized extracellular matrix that surround PV cells in the vHipp, are necessary for the sustained antidepressant response to ketamine. Disruptions in the extracellular matrix have been observed in patients with psychiatric disorders such as depression and schizophrenia (Lubbers et al., 2014). Therefore, understanding the role of PNNs in the antidepressant action of ketamine may have important implications for this novel and promising antidepressant drug .

N-methyl-D-aspartate receptor antagonists, like ketamine, produce a rapid-acting and long-lasting antidepressant effect. Although the mechanism is not completely understood, ketamine is thought to preferentially target N-methylD-aspartate receptors on fast-spiking parvalbumin-containing interneurons. The function of parvalbumin-containing interneurons is dependent on perineuronal nets, a specialized form of extracellular matrix that surrounds these cells.

Summary : Ketamine affects perinuclear networks of cells around the hippocampal cells. These cells are inhibitory to the main neuron cells and are shut down by Ketamine , thus activating dormant pathways in a depressed mind.

Depression Esketamine Ketamine

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Ketamine, a new antidepressant, has been blowing minds for decades

A scientist used the psychedelic drug in a quest for enlightenment, and it became the basis for the movie ‘Altered States’

Physician and psychoanalyst John C. Lilly. (John Bryson/Life Images Collection/Getty Images)

John C. Lilly took his first dose of ketamine to help with his chronic migraine headaches.

It worked, and soon Lilly, a renowned counterculture physician and close associate of 1960s psychedelic guru Timothy Leary, was riding increasing doses of the drug into some of the strangest research of the late 20th century.

Ketamine, first developed as an anesthetic, figured largely into two of Lilly’s most famous projects: the invention of the isolation tank and his NASA-funded efforts to communicate with dolphins.

And sometimes it got weird.

“That evening I took 150 milligrams of ketamine,” Lilly said in one interview, describing one of his frequent perceived interactions with other-dimensional beings, “and suddenly the Earth Coincidence Control Office removed my penis and handed it to me.”

After his wife came to comfort him, Lilly confirmed that he was unharmed.

Such is the unconventional, complex chemical history of ketamine, a form of which the Food and Drug Administration approved this week as the first new type of antidepressant in decades. A nasal spray known as esketamine holds great promise for people with treatment-resistant depression, researchers say.

[In biggest advance for depression in years, FDA approves novel treatment for hardest cases]

That’s only the latest use for the well-traveled drug.

Ketamine, first synthesized by a Detroit chemist in 1962, has been used as a combat zone anesthetic, an emergency room painkiller and a surgical sedative for horses. And for decades, it has also been a recreational drug, embraced by trip-seekers from the counterculture to the club scene.

By the early 1970s, the drug known as “Special K,” among other street names, had found a foothold among the growing number of LSD and hallucinogenic enthusiasts. It appeared in the pages of “The Fabulous Furry Freak Brothers” and other journals of the psychedelic age, grew in popularity, and remained a fixture into the rave movement. What its users sought was a version of the mind-body detachment effect that made it so welcome to wounded U.S. troops in Vietnam, who were its first medical users.

“Its dissociative properties were extreme,” said Tom Shroder, a former Washington Post editor and author of “Acid Test: LSD, Ecstasy and the Power to Heal.” He noted that several of the old recreational hallucinogens are now vying for new therapeutic cred.

“This is the first of the psychedelics to reach prescription status,” Shroder said. “There are a lot coming up behind it: psilocybin, MDMA [ecstasy], LSD.”

The federal government classified ketamine as a Schedule III controlled substance in 1999 in a futile effort to stop its recreational use. But in the research realm, its reputation continued to grow.

The drug has had many champions, including a recent generation of psychiatrists who have agitated for some version of it to be approved for the treatment of depression. But probably no one had a stranger history with the substance than Lilly, who was from a wealthy family from St. Paul, Minn., and had degrees in medicine and psychoanalysis.

The author of almost 20 books, he was the polymath contributor to fields including electro-neurobiology and gas pressure measurement. Lilly is credited with coining the phrase “human biocomputer,” a widely embraced metaphor of the brain as hardware and the mind as software. Leary once called his friend “a veritable Isaac Newton of the mind.”

He was also, like Leary, an enthusiastic “psychonaut,” embracing a variety of consciousness-expanding drugs in a metaphysical quest to understand the greater meaning of being. Lilly’s experience with LSD, which he described in his book “Center of the Cyclone: An Autobiography of Inner Space,” was less than positive. He had more enthusiasm for ketamine, devoting several chapters to the drug in his 1988 book, “The Scientist: A Metaphysical Autobiography.”

The drug figured in both of Lilly’s most notable works: his groundbreaking advocacy for dolphins and other cetaceans as being near-peers of humans in terms of intelligence, and his invention of the isolation tank.

He began to develop the latter in the 1950s, a dark, soundproof enclosure half filled with saline water meant to deprive a person of all external stimulus so deeper levels of the unconscious mind could emerge. In later years, he spent hours inside, carefully noting his reaction to various doses of ketamine. Lilly’s experience forms the basis of the novel and film “Altered States.”

He also used the drug in his many encounters with marine mammals, a project he worked on for decades until his death in 2001 at age 86. Lilly wrote multiple books on his belief that dolphins were capable of communication, something now widely accepted, and his goal of creating a common language with them. His work began with dissecting their brains, then connecting probes to their skulls while they were alive. Finally, in the 1960s, he and his associates were spending days with them in a lab in the Caribbean, hoping to teach them human speech. The work was funded in part by NASA; the research intrigued Carl Sagan and astrophysicists, who thought it might apply to future contact with extraterrestrials.

That project foundered over reports that the animals were being abused, including being injected with LSD. But Lilly would spend years trying to bridge the interspecies gap, often with the help of ketamine, a drug that has been many places and come a long way.

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How celastrol sensitizes brains to leptin, curbing hunger and obesity

celastrol path of action
Celastrol increases numbers of IL1R1 receptors in the brain, allowing leptin to act. (ILLUSTRATION: ELLA MARU STUDIO)

Here’s what’s known about celastrol, widely hailed in 2015 for its potent anti-obesity effects. It’s derived from the roots of the thunder god vine. It increases the brain’s sensitivity to leptin, the hormone that signals we’ve had enough to eat. It has curbed food intake by nearly 80 percent in obese mice, producing up to a 45 percent weight loss. It’s now in Phase 1 clinical trials conducted by ERX Pharmaceuticals; phase 2 studies are slated to begin this year.

What hasn’t been known is how celastrol makes the brain more sensitive to leptin. A study in today’s Nature Medicine finally provides an answer.

A team led by Umut Ozcan, MD, in the Division of Endocrinology at Boston Children’s Hospital, originally identified celastrol through a screen of more than 1,000 compounds. Ozcan later founded ERX to take celastrol and other leptin sensitizers into clinical development.

Now, Ozcan and colleagues show that celastrol works through a pro-inflammatory signaling pathway, by increasing amounts of a receptor called IL1R1. This receptor, which receives signals from the cytokine interleukin 1, is essentially the gatekeeper for celastrol’s metabolic actions, the study found.

This is a new chapter for understanding the regulation of hunger.

“If you knock out IL1R1, the leptin-sensitizing and anti-obesity effects of celastrol are completely gone,” says Ozcan, the study’s senior investigator.

Mice deficient in IL1R1 also lost celastrol’s other metabolic benefits, which include curbing insulin resistance and type 2 diabetes.

Inflammation is good?

Scientifically, the finding seems somewhat surprising. Inflammatory stimuli — cytokines or activation of inflammatory signaling pathways — had been thought to help drive the development of obesity and type 2 diabetes.

But studies published by Ozcan’s team in Nature Medicine (2011) and Cell (2017) suggest that the relationship between inflammation and obesity is more complex than previously appreciated. Those studies showed that inflammatory signaling is actually beneficial and required for keeping glucose homeostasis in control. In fact, leptin itself is a pro-inflammatory cytokine, notes Ozcan.

the thunder god vine, source of celastrol
The thunder god vine, source of celastrol (PHOTO: QWERT1234/WIKIMEDIA COMMONS)

“I believe that inflammatory signaling cascades have been wrongly regarded as the scapegoat of obesity and diabetes research,” he says. “On the contrary, our work has shown that it is probably the dysfunction of pro-inflammatory signaling pathways that contributes to the development of obesity and type 2 diabetes. The problem is that the body becomes resistant to cytokine signaling, rather than cytokine action being the problem.”

In any event, the researchers believe that it may be possible to make use of cytokine signaling, via ILR1, to alter our metabolism and help us lose weight.

Finding IL1R1

Ozcan’s team identified ILR1’s role through a stepwise approach. The researchers first investigated how celastrol changes gene expression in the hypothalamus, the part of the brain where leptin does its signaling. They created three groups: lean mice, mice made obese by overfeeding and mice that were obese because they lacked functioning leptin receptors.

By analyzing RNA in the hypothalamus in each group, Ozcan and colleagues created a list of genes whose up- or down-regulation could plausibly account for celastrol’s effects.

Eventually, their search narrowed to genes altered in the obese mice that retained their leptin receptors. IL1R1 rose to the top of the list.

Listening to leptin

Thus far, celastrol is producing encouraging weight-loss results in the early-stage clinical trials. But should it ultimately fail, the IL1R1 finding raises new potential avenues to explore.

“We will now investigate what upregulates IL1R1,” says Ozcan. “It could lead to development of new molecules for the treatment of obesity and associated diseases. This is a new chapter for understanding the regulation of hunger.”

Xudong Feng, PhD, and Dongxian Guan, PhD, of the Division of Endocrinology at Boston Children’s Hospital were co-first authors of the paper. The study was funded by the Department of Medicine at Boston Children’s Hospital, the National Institutes of Health and Fidelity Biosciences Research Initiative. Ozcan is a scientific founder, shareholder and member of the board of directors of ERX Pharmaceuticals.

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How the antidepressant ketamine rapidly awakens the brain, and why its effects vary more in women

In small doses, the anesthetic ketamine is a mildly hallucinogenic party drug known as “Special K.” In even smaller doses, ketamine relieves depression — abruptly and sometimes dramatically, steering some people away from suicidal thoughts. Studies indicate that ketamine works in 60 to 70 percent of people not helped by slower-acting SSRIs, the usual drugs for depression.

Two ketamine-like drugs are in the clinical pipeline, and, as of this week, one appears close to FDA approval. With no significant new antidepressant in more than 30 years, anticipation is high. Yet no one has pinned down how low-dose ketamine works. Studies have implicated various brain neurotransmitters and their receptors — serotonin, dopamine, glutamate, GABA receptors, opioid receptors — but findings have been contradictory.

“We felt it was time to figure this out once and for all,” says neuroscientist Takao Hensch, PhD.

In a study published late last month in Molecular Psychiatry, the laboratories of Hensch and Michela Fagiolini, PhD, both in the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, pinpointed ketamine’s mechanism of action. And, unexpectedly, they found evidence that its efficacy in females varies with the menstrual cycle — suggesting the need to time treatment accordingly.

Parsing ketamine’s action

It has widely been held that ketamine relieves depression by blocking NMDA, a glutamate receptor. Glutamate is an excitatory neurotransmitter, making neurons more active, more communicative and more likely to form new connections. So logic would suggest that blocking its receptor, depriving neurons of excitatory signals, would make the brain even more sluggish and indifferent to stimulation — worsening depression.

“Ketamine, by blocking the NMDA receptor, should dampen neural activity,” says Hensch. “But the paradox is that it makes neural activity stronger — it awakens the brain.”

The research team, led by postdoctoral fellows Nathalie Picard, PhD, and Anne Takesian, PhD, teased out the puzzle in mice using a genetic approach. They deleted the gene for one component of the NMDA receptor, called the 2A subunit. And they deleted it only in a certain kind of neuron in the brain, the parvalbumin interneurons. Then they gave the mice ketamine.

Awakening the brain

The investigators first measured the firing of neurons in the cerebral cortex, and found that it was rapidly enhanced by ketamine — except in mice whose NMDA receptors were deleted. In a swim test, the classic model for measuring antidepressant activity, mice given ketamine worked more vigorously than untreated mice to rescue themselves from the cold water — but again, only when their NMDA receptors were intact.

“With ketamine, the neurons became more active,” says Hensch. “But they were not rescued if the 2A subunit was deleted. We think this is the best evidence yet that it’s an NMDA receptor on a particular kind of cell that’s important.”

Parvalbumin circuits in the cerebral cortex

That cell type explains the paradox of ketamine’s action. Small in number and size, parvalbumin neurons synchronize the electrical activities of other brain cells. They are inhibitory in nature, depressing the activity of the brain circuits around them. Blocking glutamate eliminates this natural inhibition, exciting the circuits as a whole. This, Hensch believes, allows the brain to be more sensitive and responsive to sensory input, lifting it out of its depressive funk.

Sex-specific effects

The second part of the study was more surprising: Female mice responded less consistently to ketamine.

“We found that drug action was variable – sometimes ketamine would boost activity, sometimes not,” says Hensch.

When Picard and Takesian looked at females during different stages of the estrous cycle, they found that ketamine had little effect during the follicular phase (which in women starts on the first day of menstruation and ends with ovulation). During this time, parvalbumin neurons had fewer glutamate receptors bearing the 2A subunit.

Hensch and Fagiolini think clinical trials of ketamine should take this into account.  “In the clinical literature, ketamine effectiveness varies widely — from 40 to 80 percent,” says Fagiolini. “The timing of treatment in women may explain that variability.”

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Insights from Rett syndrome

Hensch and Fagiolini took cues from their prior work on Rett syndrome, a rare neurologic condition in girls that causes vision loss, autism and other complications. In 2012, they showed in mice that the Rett mutation disrupts brain wiring early in development, such that parvalbumin connections were too abundant, forming many more synapses than normal. The end result was an excess of inhibition such that brain activity died down.

“The parvalbumin cells were maturing faster than normal,” says Fagiolini. “Through electrical recordings, we showed that the brain is quite normal early on, but activity is gradually lost — consistent with the ‘silencing’ of the brain that we observe in Rett syndrome.”

But when Hensch and Fagiolini deleted the NMDA receptor and, in particular, the 2A subunit, in the brains of mice with Rett syndrome, they slowed down parvalbumin-cell maturation. This prevented vision loss in the mice, mirroring reduced disease severity.

Follow-up work in Fagiolini’s lab showed that low-dose ketamine, given daily, restored normal brain circuitry, slowed the progression of Rett symptoms and extended the animals’ life span. This insight, among others, prompted a multicenter clinical trial of ketamine for Rett syndrome in girls aged 6-12, which opened in 2018 at Boston Children’s and six other centers.

The new work suggests that trials in women and older girls with Rett syndrome, an X-linked disorder, should be mindful of the menstrual cycle and when it begins in younger patients.

Cleaning up ketamine’s action

Ketamine is a “dirty” drug that acts on many receptors with many side effects, and is thought to be addictive. But the researchers think it may be possible to find a cleaner, safer antidepressant that acts through the NMDA receptor, and specifically through the 2A subunit.

Hensch’s lab is also interested in exploring the potential usefulness of modulating parvalbumin circuits in psychosis and other conditions in which these cells are altered. Abnormalities in these cells are believed to play a pivotal role in autism, schizophrenia and other neurodevelopmental disorders.

“We’re interested in how these cells develop faster or slower in different diseases,” says Hensch.

The study was funded by the Silvio Conte Center of the National Institute of Mental Health (P50MH094271), the University of Tokyo International Research Center for Neurointelligence (IRCN), the Rett Syndrome Research Trust, Rett syndrome.org, the National Institute of Neurologic Disorders and Stroke (R01 NS095959), the National Eye Institute (R01 EY013613), Pfizer, the Nancy Lurie Marks Family Foundation and the Canadian Institute for Advanced Research.

More research from the Hensch and Fagiolini labs.

Depression Esketamine

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Ketamine For Severe Depression: ‘How Do You Not Offer This Drug To People?’

Ketamine Infusion Center | 703-844-0184 | NOVA Health Recovery | Dr. Sendi | Alexandria, Va 22306
Ketamine Infusion Center | 703-844-0184 | NOVA Health Recovery | Dr. Sendi | Alexandria, Va 22306

Gerard Sanacora, a professor of psychiatry at Yale University, has treated hundreds of severely depressed patients with low doses of ketamine, an anesthetic and popular club drug that isn’t approved for depression.

This sort of “off-label” prescribing is legal. But Sanacora says other doctors sometimes ask him, “How can you be offering this to patients based on the limited amount of information that’s out there and not knowing the potential long-term risk?”

Sanacora has a simple answer.

“If you have patients that are likely to seriously injure themselves or kill themselves within a short period of time, and they’ve tried the standard treatments, how do you not offer this treatment?” he says.

More and more doctors seem to agree with Sanacora.

Dozens of clinics now offer ketamine to patients with depression. And a survey of providers in the U.S. and Canada showed that “well over 3,000” patients have been treated so far, Sanacora says.

A number of small studies have found that ketamine can do something no other drug can: it often relieves even suicidal depression in a matter of hours in patients who have not responded to other treatments.

Ketamine’s potential as an antidepressant was recognizedmore than a decade ago. And studies done since then provide “compelling evidence that the antidepressant effects of ketamine infusion are both rapid and robust, albeit transient,” according to a consensus statement from a task force of the American Psychiatric Association. Sanacora is one of the task force members.

But there are still a lot of unanswered questions about ketamine, says James Murrough, an assistant professor of psychiatry and neuroscience at the Icahn School of Medicine at Mt. Sinai in New York.

“We haven’t had large-scale trials. We don’t know how much or how often it should be given for it to be effective or safe,” says Murrough, who is an author of a review of ketamine published in the journal Nature Reviews Drug Discovery.

Doctors know a lot about the short-term effects of ketamine because it has been used as an anesthetic in emergency rooms for decades. But there’s still not much information about the effects of using ketamine for years.


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A vial of ketamine, an anesthetic and club drug that is sometimes used to treat severe depression.Wikipedia

That’s worrisome because ketamine’s antidepressant effect tends to wear off after a few days or weeks, meaning patients need repeated infusions to keep depression at bay, Murrough says.

Still, Murrough thinks the case for using ketamine is much stronger than it was just a few years ago.

“There’s warranted caution that’s balanced with an optimism that says we’ve never had a new medication for depression since the era of Prozac,” Murrough says.

Prozac arrived in the 1980s, and became the first of a new class of depression drugs that target the neurotransmitter serotonin.

Ketamine acts on a different neurotransmitter called glutamate. The drug’s success has pharmaceutical companies excited about the possibility of creating a whole new class of drugs for depression, Murrough says.

“Companies are reopening programs,” he says. “They are pulling [old] drugs off the shelf that they know act on the glutamate system.”

One promising candidate is a chemical sibling of ketamine called esketamine. It’s now in the final phase of testing before consideration by the Food and Drug Administration, which designated esketamine as a breakthrough therapy.

And esketamine is just one of several ketamine-like drugs in development, says Sanacora, who consults for companies developing these drugs.

“This is probably the most interesting and exciting new development that I’ve seen in my career, and probably going back over the past 50 to 60 years,” he says.

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