Category Archives: Ketmamine

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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

Ketamine Virginia Link

Long known as a party drug, ketamine now used for depression, but concerns remain

What Makes the Ketamine-Based Drug for Depression So Different?

On Tuesday (March 5), the U.S. Food and Drug Administration (FDA) approved a ketamine-like nasal spray for patients with depression who haven’t responded to other treatments.

But what makes this newly approved treatment so different?

The drug, called Spravato and made by Janssen Pharmaceuticals, contains the active ingredient esketamine. This substance has the same molecular formula as ketamine but a different chemical structure. (In other words, it contains the same type and number of elements but in a different configuration.) Ketamine is typically used as an anesthetic, but it’s also been used as an illicit party drug.

One reason experts are excited about the nasal spray is that its effects can be seen within several hours to days. Other antidepressants, meanwhile, can take weeks to start working

Antidepressants work by regrowing brain cells and the connections between them, and ketamine appears to have the same effects, said David Olson, an assistant professor of chemistry, biochemistry and molecular medicine at the University of California, Davis. But, these effects likely start much sooner than with other antidepressants, he said.

Still, it’s not entirely clear how the drug works.

Ketamine-like drugs are “dirty”, meaning they likely hit a variety of targets in the brain, Olson told Live Science. “There are a lot of very interesting hypotheses out there, [and] many of them are probably partially valid.”

One idea is that ketamine treats depression by blocking a neurotransmitter called glutamate from binding to the NMDA receptor, and stopping signals from cascading across the brain, Dr. Alan Schatzberg, a professor of psychiatry and behavioral sciences at the Stanford University School of Medicine, told Live Science.

Glutamate is a chemical that brain cells use to send signals to other brain cells. But high levels of it can cause over-excitement in the brain, which can, in turn, damage brain cells.

A more controversial idea is that ketamine binds to opioid receptors, causing a release of naturally occurring opioids in the body. Schatzberg and his team published a small study on this last summer in which they gave patients with depression ketamine twice — once after receiving an opioid-blocking drug, and once after receiving a placebo in place of the opioid blocker. The two treatments took place about a month apart, and neither the participants nor the researchers knew whether patients received the opioid blocker or the placebo. The study found that the patients responded well to the ketamine treatment if they didn’t receive the opioid-blocking drug, but ketamine had no effect on those that did, suggesting an opioid-like role.

This hypothesis has some experts concerned about ketamine-based drugs as a depression treatment.

“My concern about this compound is that it is a disguised form of opiates,” said Dr. Mark George, a distinguished professor of psychiatry, radiology and neurosciences at the Medical University of South Carolina. While George said he is “overjoyed” for the prospect of a new treatment option, “I’m alarmed that there is pretty clear evidence [that] the way ketamine works is through the opioid system.”

If this is the mechanism that ketamine acts through to treat depression, its effects won’t last and people might develop a tolerance to the drug, possibly even becoming addicted, George told Live Science. But if its antidepressant effects come from other mechanisms, such as blocking the NMDA receptor, then “that’s good,” he said.

Olson, however, said that he is less convinced by the opioid hypothesis and thinks more work needs to be done before ringing the alarm bells.

What’s more, the new drug will see limited use. The medication comes with a risk of sedation and dissociation, such as difficulty with judgment, attention and thinking. Because of that, the nasal spray was approved to be used only under a “restricted distribution system,” according to a statement from the FDA.

This means that only patients with severe depression who haven’t responded to at least two antidepressant treatments can receive the drug. In addition, the treatment is administered only in doctor’s offices, and patients must stay in the office and be monitored for several hours after receiving the treatment.

Ultimately, despite some potential problems with the newly approved drug, experts are hopeful it will come through strong.

“I think that the FDA approval of ketamine is a huge landmark in the history of treating neuropsychiatric diseases,” Olson said. “Ketamine really represents a leap forward in terms of new ideas for attacking depression and related neuropsychiatric diseases.”



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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

Ketamine Virginia Link

Twitter feed Ketamine – Ablow

Ketamine Seems to Ease Depression. We’ll Soon See What Else It Does.

Clinical trials are not enough to prove any drug is safe and effective – especially one that could be as widely used as Johnson & Johnson’s depression drug esketamine, a slightly altered form of the street drug ketamine. The FDA approval process is a balancing act, weighing safety and efficacy testing against the need to get potentially life-saving drugs out as soon as possible.

An advisory panel to the FDA decided this month that the benefits outweigh the risks, and approval is expected soon. But scientists who study depression say there’s a lot more to learn about esketamine’s long-term effects.

While best known as a recreational drug, ketamine has been used since the 1970s as an anesthetic, in doses much higher than what’s likely to be given to depression patients. The trials so far seem to show that the drug is not highly addictive, according to a story in the medical website STAT. But time will tell.

The most promising clinical trials followed people whose depression had been resistant to conventional therapy. Fifty percent of patients improved when given conventional therapy plus a placebo, as compared to 70 percent who got conventional therapy and esketamine.

Taking the drug will be a lot more complicated than taking Prozac. It’s been formulated so that it can be delivered as a nasal spray, but people have to get the drug at a doctor’s office, and they won’t be allowed to drive for at least 24 hours, said Gerard Sanacora, a Yale University psychiatrist who has been involved in the clinical trials.

He said he believes there’s potential for benefit, because the drug works for some people who get no relief from conventional treatments and because works faster, which might even prevent suicide. But there’s a lot more to learn about the drug’s potential long-term consequences. So far it looks like people will get two treatments a week to start, then one for maintenance. But scientists don’t know whether it can be tapered down further, or discontinued, and whether there’s a risk for relapse, he said.

Sanacora said that ketamine is based on a very different model of how depression works. Standard therapy is based on the principle that depression is a chemical imbalance involving the transmitting chemical serotonin. But an alternative view started to take shape in the 1990s that depression was more of a problem with the connections between neurons, triggered by chronic stress and mediated by something called the glutaminergic system.

Because ketamine interacts with this system, researchers started testing it as a depression drug. Although it seems effective, there’s still no agreement on how depression actually works – and there is some concern that it might work very differently in different patients.

Ketamine can affect cardiovascular health, and in the short term can cause patients to lose their sense of their bodies’ position in space – the sense of proprioception. They sometimes feel their arms are floating.

That hasn’t stopped people from flocking to clinics to get treated with IV ketamine infusions for depression and other problems. This is legal because the drug is approved for anesthesia, and prescribers can use it off-label for other purposes. An investigation by the medical website STAT raised concerns that clinic staff didn’t have the necessary expertise, and there was considerable marketing hype in many cases. The infusions cost between $350 and $1,000 each, and can go on for five or six treatments.

Another red flag popped up last week when the Boston Globe ran a storyabout three women who claim to have been sexually abused by psychiatrist Keith Ablow – a frequent commentator for Fox News. The Globe reported that Ablow was treating the women with ketamine, and one expert cited in the lawsuits said a patient had become “very dependent on this medication and dependent on Dr. Ablow to supply it.”

Ablow’s Twitter feed is full of positive stories about ketamine in places such as Reader’s Digest, followed by a phone number to call for a “free ketamine screening.” The allegations illustration that it’s not just patients that will need to be tracked for abuse, but the doctors as well.

On the positive side, FDA approval would give patients who want the drug a standardized treatment that would be covered by many insurance plans. Approval also creates an opportunity to collect data on longer-term use. (An earlier column exploring the promise of big data in medicine points out that clinical trials are often not long-running enough or big enough to catch even deadly side effects.)

Yale’s Sanacora thinks of the next series of trials as Phase 4. Sanacora also brought up what he poignantly called the “Flowers for Algernon” effect, referring to the short story in which the main character, Charlie Gordon, is treated for an intellectual disability. The treatment works, but eventually wears off, leaving Charlie back where he started. The disappointment makes for a tragic tale. An arc like this would be the last thing depression patients need – though if no other treatment is helping, it might be a risk worth taking.

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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

Ketamine Virginia Link

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

Ketamine Virginia Link

Ketamine Works as a Fast-Acting Antidepressant, But the Full Effects Are Still Unknown

Ketamine Works as a Fast-Acting Antidepressant, But the Full Effects Are Still Unknown

etamine leads something of a double life, straddling the line between medical science and party drug. Since it’s invention in the early 1960s, ketamine has enjoyed a quiet existence as a veterinary and pediatric anesthetic given in high doses. But in a second, wilder life, ketamine’s effects at lower doses—a profound sense of dissociation from self and body—became an illicit favorite among psychedelic enthusiasts. Pioneering neuroscientist John Lilly, who famously attempted to facilitate communication between humans and dolphins, used the drug in the late 1970s during experiments in sensory deprivation tanks. By the 1990s, the drug had made its way to the dance floor as “special K.”

More recently, ketamine has taken on a third, wholly unexpected role. Since the early 2000s, the drug has been studied as a uniquely powerful medication for treating severe depression and obsessive-compulsive disorder (OCD). When given as an intravenous infusion, ketamine can lift symptoms of depression and OCD from patients who fail to respond to common antidepressants like Prozac and even resist treatments like electroconvulsive therapy (ECT).

Exactly how ketamine produces antidepressant effects remains unclear, however. Antidepressants like Prozac are Serotonin Reuptake Inhibitors (SSRIs) that increase levels of the neurotransmitter serotonin in the brain, which is believed to boost mood. Ketamine’s main mechanism of action to produce dissociative anesthetic effects, on the other hand, depends on another neurotransmitter, glutamate.

“The prevailing hypothesis for ketamine’s antidepressant effect is that it blocks a receptor (or docking port) for glutamate,” says Carolyn Rodriguez, a professor of psychiatry at Stanford who has conducted some of the pioneering research into ketamine as an OCD treatment.

However, new research suggests that ketamine’s influence on glutamate receptors, and specifically the NMDA receptor, may not be the sole cause of its antidepressant effects. According to a recent study in the American Journal of Psychiatry by Rodriguez and her Stanford colleagues, ketamine might also activate a third system in the brain: opioid receptors.

Ketamine is known to bind weakly to the mu opioid receptor, acting as an agonist to produce a physiological response at the same site in the brain where narcotics like morphine exert their influence. It’s also known that opioids can have antidepressant effects, says Alan Schatzberg, a professor of psychiatry at Stanford and co-author of the new study.

It never made sense to Schatzberg that ketamine’s antidepressant effects were a result of blocking the glutamate receptors, as attempts to use other glutamate-blocking drugs as antidepressants have largely failed. The Stanford psychiatrist, who has spent his career studying depression, wondered if researchers were unknowingly activating opioid receptors with ketamine.

“You could test this by using an antagonist of the opioid system to see if you blocked the effect in people who are ketamine responders,” he says. “And that’s what we did.”

The researchers enlisted 12 subjects with treatment-resistant depression and gave them either an infusion of ketamine preceded by a placebo, or ketamine preceded by a dose of naltrexone, an opioid receptor blocker. Of those, seven subjects responded to the ketamine with placebo, “and it was very dramatic,” Schatzberg says, with depression lifting by the next day. “But in the other condition, they showed no effect,” suggesting it was the opioid receptor activity, not blocking glutamate receptors, that was responsible.

While opioid blockers prevented ketamine from activating the associated receptors, it did not block the drugs dissociative effects, suggesting dissociation alone won’t affect depression. “It’s not that, ‘hey, we’ll get you a little weird and you’ll get the effect,’” Schatzberg says.

The appeal of ketamine’s use as an antidepressant is clear enough. While more typical antidepressants may require six to eight weeks to produce benefits, ketamine works within hours.

“Our patients are asked to hang in there until the medication and talk therapy takes effect,” says Carlos Zarate, chief of the experimental therapeutics and pathophysiology branch of the National Institute of Mental Health (NIMH) who was not associated with the new study. While waiting for traditional treatments to kick in, patients “may lose their friends or even attempt suicide.”

But the study linking ketamine to opioid activity means an extra dose of caution is required. While ketamine acts quickly, the anti-depressive effects of the drug only last for a few days to a week, meaning repeat doses would be needed in practice. Researchers and clinicians should consider the risk of addiction in long-term use, Schatzberg says. “You’re going to eventually get into some form of tolerance I think, and that’s not good.”

However, the new finding is based on just seven subjects, and it still needs to be replicated by other scientists, says Yale professor of psychiatry Greg Sanacora, who was not involved in the new study. And even if the trial is replicated, it would not prove ketamine’s opioid activity is responsible for its antidepressant effects.

“It doesn’t show that at all,” says Sanacora, who studies glutamate, mood disorders and ketamine. “It shows that the opioid system needs to be functioning in order to get this response.”

Sanacora compares the new study to using antibiotics to treat an ear infection. If you administered an additional drug that blocks absorption of antibiotics in the stomach, you would block treatment of the ear infection, but you wouldn’t conclude that antibiotics fight ear infections through stomach absorption—you just need a normally functioning stomach to allow the antibiotic to do its job. Similarly, opioid receptors might need to be functioning normally for ketamine to produce antidepressant effects, even if opioid activity is not directly responsible for those effects.

Complicating matters further, placebos often cause patients to experience less pain, but opioid blockers like naltrexone have been shown to prevent this response, according to Sanacora. It could be, he suggests, that all the apparatus of the clinic—the nursing staff, the equipment—exerted a placebo effect that is mediated by the brain’s opioid system, and the patients who received naltrexone simply did not respond to that placebo effect

“That’s a very important and powerful tool that is in all of medicine, not just in psychiatry,” Sanacora says. “And we know that the opiate system is involved, to some extent, in that type of response.”

It’s also possible, the researchers note in the paper, that ketamine’s action at the glutamate receptor is still important. “Ketamine acts in three distinct phases—rapid effects, sustained effects and return to baseline,” Rodriguez says. Opioid signaling may turn out to mediate ketamine’s rapid effects, while “the glutamate system may be responsible for the sustaining effects after ketamine is metabolized.”

One interpretation is that ketamine blocks glutamate receptors on neurons that are inhibitory, meaning they signal other neurons to fire fewer signals. By blocking these neurons from firing, ketamine may enhance glutamate activity in the rest of the brain, producing anti-depressive effects that persist after the opioid activity dies down.

“The reality is it’s in a gray zone,” Sanacora says. “This is just one small piece of a very large puzzle or concern that we really need to look at the data in total.”

That data is forthcoming. Results from a Janssen Pharmaceuticals clinical trial using esketamine, an isomer of ketamine, and involving hundreds of subjects will soon become public, according to Sanacora, who has consulted for the company. And at NIMH, Zarate and colleagues are studying hydroxynorketamine, a metabolite of ketamine that may provide the same benefits but without the dissociative side effects

Ketamine Works as a Fast-Acting Antidepressant, But the Full Effects Are Still Unknown

A new study suggests that ketamine activates the brain’s opioid receptors, complicating its use to treat clinical depression

Ketamine Syringe
Ketamine syringe, 10mg held by a healthcare professional. (Peter Cripps / Alamy Stock Photo)

By Jon KelveySEPTEMBER 11, 2018777110231.1K

Ketamine leads something of a double life, straddling the line between medical science and party drug. Since it’s invention in the early 1960s, ketamine has enjoyed a quiet existence as a veterinary and pediatric anesthetic given in high doses. But in a second, wilder life, ketamine’s effects at lower doses—a profound sense of dissociation from self and body—became an illicit favorite among psychedelic enthusiasts. Pioneering neuroscientist John Lilly, who famously attempted to facilitate communication between humans and dolphins, used the drug in the late 1970s during experiments in sensory deprivation tanks. By the 1990s, the drug had made its way to the dance floor as “special K.”

More recently, ketamine has taken on a third, wholly unexpected role. Since the early 2000s, the drug has been studied as a uniquely powerful medication for treating severe depression and obsessive-compulsive disorder (OCD). When given as an intravenous infusion, ketamine can lift symptoms of depression and OCD from patients who fail to respond to common antidepressants like Prozac and even resist treatments like electroconvulsive therapy (ECT).

Exactly how ketamine produces antidepressant effects remains unclear, however. Antidepressants like Prozac are Serotonin Reuptake Inhibitors (SSRIs) that increase levels of the neurotransmitter serotonin in the brain, which is believed to boost mood. Ketamine’s main mechanism of action to produce dissociative anesthetic effects, on the other hand, depends on another neurotransmitter, glutamate.

“The prevailing hypothesis for ketamine’s antidepressant effect is that it blocks a receptor (or docking port) for glutamate,” says Carolyn Rodriguez, a professor of psychiatry at Stanford who has conducted some of the pioneering research into ketamine as an OCD treatment.

However, new research suggests that ketamine’s influence on glutamate receptors, and specifically the NMDA receptor, may not be the sole cause of its antidepressant effects. According to a recent study in the American Journal of Psychiatry by Rodriguez and her Stanford colleagues, ketamine might also activate a third system in the brain: opioid receptors.

Ketamine is known to bind weakly to the mu opioid receptor, acting as an agonist to produce a physiological response at the same site in the brain where narcotics like morphine exert their influence. It’s also known that opioids can have antidepressant effects, says Alan Schatzberg, a professor of psychiatry at Stanford and co-author of the new study.

It never made sense to Schatzberg that ketamine’s antidepressant effects were a result of blocking the glutamate receptors, as attempts to use other glutamate-blocking drugs as antidepressants have largely failed. The Stanford psychiatrist, who has spent his career studying depression, wondered if researchers were unknowingly activating opioid receptors with ketamine.

“You could test this by using an antagonist of the opioid system to see if you blocked the effect in people who are ketamine responders,” he says. “And that’s what we did.”

The researchers enlisted 12 subjects with treatment-resistant depression and gave them either an infusion of ketamine preceded by a placebo, or ketamine preceded by a dose of naltrexone, an opioid receptor blocker. Of those, seven subjects responded to the ketamine with placebo, “and it was very dramatic,” Schatzberg says, with depression lifting by the next day. “But in the other condition, they showed no effect,” suggesting it was the opioid receptor activity, not blocking glutamate receptors, that was responsible.

While opioid blockers prevented ketamine from activating the associated receptors, it did not block the drugs dissociative effects, suggesting dissociation alone won’t affect depression. “It’s not that, ‘hey, we’ll get you a little weird and you’ll get the effect,’” Schatzberg says.

The appeal of ketamine’s use as an antidepressant is clear enough. While more typical antidepressants may require six to eight weeks to produce benefits, ketamine works within hours.

“Our patients are asked to hang in there until the medication and talk therapy takes effect,” says Carlos Zarate, chief of the experimental therapeutics and pathophysiology branch of the National Institute of Mental Health (NIMH) who was not associated with the new study. While waiting for traditional treatments to kick in, patients “may lose their friends or even attempt suicide.”

<

A treatment that works within 24 hours? “That’s huge.”

A vial of ketamine. The drug is used primarily as an anesthetic but is gaining popularity as an effective antidepressant.
A vial of ketamine. The drug is used primarily as an anesthetic but is gaining popularity as an effective antidepressant. (Wikimedia Commons)

But the study linking ketamine to opioid activity means an extra dose of caution is required. While ketamine acts quickly, the anti-depressive effects of the drug only last for a few days to a week, meaning repeat doses would be needed in practice. Researchers and clinicians should consider the risk of addiction in long-term use, Schatzberg says. “You’re going to eventually get into some form of tolerance I think, and that’s not good.”

However, the new finding is based on just seven subjects, and it still needs to be replicated by other scientists, says Yale professor of psychiatry Greg Sanacora, who was not involved in the new study. And even if the trial is replicated, it would not prove ketamine’s opioid activity is responsible for its antidepressant effects.

“It doesn’t show that at all,” says Sanacora, who studies glutamate, mood disorders and ketamine. “It shows that the opioid system needs to be functioning in order to get this response.”

Sanacora compares the new study to using antibiotics to treat an ear infection. If you administered an additional drug that blocks absorption of antibiotics in the stomach, you would block treatment of the ear infection, but you wouldn’t conclude that antibiotics fight ear infections through stomach absorption—you just need a normally functioning stomach to allow the antibiotic to do its job. Similarly, opioid receptors might need to be functioning normally for ketamine to produce antidepressant effects, even if opioid activity is not directly responsible for those effects.

Complicating matters further, placebos often cause patients to experience less pain, but opioid blockers like naltrexone have been shown to prevent this response, according to Sanacora. It could be, he suggests, that all the apparatus of the clinic—the nursing staff, the equipment—exerted a placebo effect that is mediated by the brain’s opioid system, and the patients who received naltrexone simply did not respond to that placebo effect.

“That’s a very important and powerful tool that is in all of medicine, not just in psychiatry,” Sanacora says. “And we know that the opiate system is involved, to some extent, in that type of response.”

It’s also possible, the researchers note in the paper, that ketamine’s action at the glutamate receptor is still important. “Ketamine acts in three distinct phases—rapid effects, sustained effects and return to baseline,” Rodriguez says. Opioid signaling may turn out to mediate ketamine’s rapid effects, while “the glutamate system may be responsible for the sustaining effects after ketamine is metabolized.”

One interpretation is that ketamine blocks glutamate receptors on neurons that are inhibitory, meaning they signal other neurons to fire fewer signals. By blocking these neurons from firing, ketamine may enhance glutamate activity in the rest of the brain, producing anti-depressive effects that persist after the opioid activity dies down.

“The reality is it’s in a gray zone,” Sanacora says. “This is just one small piece of a very large puzzle or concern that we really need to look at the data in total.”

That data is forthcoming. Results from a Janssen Pharmaceuticals clinical trial using esketamine, an isomer of ketamine, and involving hundreds of subjects will soon become public, according to Sanacora, who has consulted for the company. And at NIMH, Zarate and colleagues are studying hydroxynorketamine, a metabolite of ketamine that may provide the same benefits but without the dissociative side effects.

The ultimate goal of all this research is to find a ketamine-like drug with fewer liabilities, and that aim is bringing researchers back to the fundamentals of science.

“For me, one of the exciting parts of this study is that it suggests that ketamine’s mechanism is complicated, it acts on different receptors beyond glutamate and is the start of this exciting dialogue,” Rodriguez says. “Sometimes great science raises more questions than answers.”

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Ketamine: Key Predictor of Treatment Response for MDD Identified

 

 

I am going to link into a few articles that discuss a phenomena that I have observed in the office setting at NOVA Health Recovery (Alexandria, Va 703-844-0184) for our Ketamine infusions in depressed and PTSD patients. The best long term results seem to occur when the individual has a slightly more dissociative experience during the infusion.  A lot of times I will give an initial boost to the medication at the start to get that state of mind going. Studies below have hinted that the slight dissociation actually improves outcomes:

Ketamine: Key Predictor of Treatment Response for MDD Identified  < Medscape article

 

Ketamine: Key Predictor of Treatment Response for MDD Identified

Nancy A. Melville

 

April 12, 2018

WASHINGTON — More intense dissociative symptoms exhibited during ketamine infusion for severe depression, particularly depersonalization, may be key predictors of treatment response. In addition, new safety and efficacy data for off-label use of the drug are encouraging.

 

Mark Niciu, MD, PhD, of the National Institute of Mental Health (NIMH), and colleagues analyzed three studies involving 126 patients with treatment-resistant depression. They found a significant association between dissociative symptoms experienced during infusion and reductions in depressive symptoms, as reflected in some, but not all, dissociation subscale measures.

 

“The findings suggest that mechanistic similarities may exist between ketamine-induced depersonalization and antidepressant response, although off-target effects cannot be excluded,” Niciu told delegates attending the Anxiety and Depression Association of America (ADAA) Conference 2018.

The results were also published in the May issue of the Journal of Affective Disorders.

In another presentation at the ADAA conference, Samuel Wilkinson, MD, assistant director of the Depression Research Program at Yale University, New Haven, Connecticut, reported details from his institution’s experience with the use of ketamine during a period of more than 30 months in patients with severe and treatment-resistant mood disorders.

 
 

Among 50 patients who received one to four treatments, the response rate, defined as a 50% improvement in symptoms, was approximately 50%; the remission rate was 27.3%.

In a subset of 14 patients who received 12 to 45 total treatments during a period of 14 to 126 weeks, there was no evidence of cognitive decline or delusions, as measured with the CogState cognitive assessment tool, Wilkinson reported.

Soaring Interest

Because conventional antidepressants can take weeks if not months to reach full effect and are completely ineffective in many patients, interest in ketamine, an N-methyl-d-aspartate receptor antagonist, as a rapid-acting treatment for severe mood disorders has soared in recent years, noted Niciu.

 

Previous studies have reported significant improvements in depression following a single ketamine infusion, with improvements lasting from several days to a week. However, not everyone responds to ketamine.

 

In the new study, 84 of the 126 participants had major depressive disorder, and 42 had bipolar depression. All were treated with the standard ketamine treatment for depression, consisting of a single subanesthetic dose (0.5 mg/kg) delivered by infusion over 40 minutes.

 

Patients were followed for at least 1 week post infusion and, in one of the three studies that were assessed, for up to 28 days.

 

In one of the studies, dissociative effects, measured using the Clinician-Administered Dissociative States Scale (CADSS) at baseline and at the end of infusion, were associated with symptoms of depression, as measured with the Hamilton Depression Rating Scale (HDRS-17), at day 7 following the infusion (P = .04).

 

Scores on the depersonalization subscale of the CADSS were related to percentage change in HDRS-17 score in all three studies and at all time points (P = .04).

 

Scores on the subscale of derealization were associated with percentage change in HDRS score on day 7 post infusion in one study (P = .01).

 

No association was observed between amnesia symptoms during infusion and reduction in depression, as reflected in percentage change in HDRS score.

 

Mechanistic Similarities

“What really jumped out at us was the depersonalization subscale,” Niciu said.

 

He speculated that depersonalization in particular may relate to some of the deeper aspects of depression, more so than derealization, which involves detachment from reality, or amnesia.

 

“There might be mechanistic similarities between depersonalization and an antidepressant response,” Niciu explained.

 

“These are people with a highly introspective disorder and are often focused on their inner self. If you can detach them from that for a period of time and disconnect them from the subjective sensations, then that may result in a better antidepressant response, but that’s a hypothesis,” he said.

 

The findings suggest that the use of the depersonalization scale could represent a relatively easy way to assess the possibility of the patient’s responding to ketamine.

 

“In the clinical setting, if someone is administering ketamine and doesn’t have much time and just wants to get a sense of how a patient might respond, the CADSS depersonalization subscale is something they might want to administer,” Niciu said.

 

“It is easy to administer — it’s only five items, and those who tend to score higher on that subscale may be more likely to be responders,” he added.

 

Relevance Questioned

The study was an extension of earlier research from the investigators linking the degree of dissociative symptoms with ketamine’s antidepressant effects.

 

On the basis of those findings, some clinicians already try to achieve the effects in order to evoke a better response, said Sanjay Mathew, MD, professor of psychiatry and behavioral sciences, Baylor College of Medicine and the Michael E. Debakey VA Medical Center, Houston, Texas, while commenting on the study at the meeting.

 

“Often, anesthesiologists and psychiatrists at ketamine clinics will start at 0.5 mg/kg and titrate the dose to mild dissociation,” said Matthew. “They often want the patient to feel buzzed, because that’s when they feel confident that they’ve hit the ‘sweet spot’ of NMDA modulation.”

 

He noted that another NIMH study of 99 patients, which is currently under review, showed that the best outcomes, as reflected in scores on depression scales, were achieved with the standard 0.5 mg/kg dose in comparison with the 1.0 mg/kg dose and the very low dose of 0.1 mg/kg, which were associated with a high degree of dissociation.

 

“Clearly, the message from that study is that you don’t need to dissociate to get better,” he said.

 

Nevertheless, “the issue is fascinating, with high clinical relevance in terms of how clinicians are using ketamine in the community,” Mathew said.

 

However, Wilkinson noted that he has not seen similar patterns in his patients who were treated with ketamine, and he questioned the use of the CADSS tool for determining dissociation symptoms in the study.

 

“We have not observed that the level of dissociation and depersonalization predict response,” he told Medscape Medical News.

 

“I am skeptical of this finding, as the CADSS instrument was not designed for use in ketamine studies and in my opinion does not do a great job at capturing this phenomenon related to ketamine,” he added.

 

Wilkinson noted that the dissociative symptoms that can occur with ketamine treatment do not appear to subside after multiple infusion sessions.

 

“In my experience treating patients, there seem to be a group of patients who always develop fairly significant symptoms, even though they have been treated 20 times or more with ketamine,” he said.

 

Longer-term Outcomes

During the presentation of his own study, Wilkinson reported that 21 participants (38%) were men and 96% were being treated with concomitant medications during the acute course. These medications included antidepressants (72.2%), antipsychotics (53.7%), mood stabilizers (37%), lithium (18.5%), and sedatives/hypnotics (50%).

 

Patients were initially treated intravenously with a single or double infusion of 0.5 mg/kg over 40 minutes. However, patients were later transitioned to a four-dose protocol administered twice per week over 2 weeks.

 

The response rate was about 50%, and the remission rate was 27.3% among 50 patients who received one to four treatments.

 

Although there was no evidence of cognitive decline or delusions, one person discontinued infusion because of intolerability, one discontinued because of hypertension, one experienced relapse of cannabis use disorder, and three required rehospitalization for suicidal ideation or suicide attempts.

 

There were two completed suicides, one occurring 10 months after last contact with the program, and one 4 months after last contact.

 

Wilkinson noted that the 50% response rate is somewhat lower than rates reported in clinical trials, which may reflect a real-world setting.

 

“This is sometimes called the ‘efficacy-effectiveness gap’ and is not really surprising, because clinical trials are usually done in ideal conditions, whereas community practice represents real-world conditions and the patients are generally sicker and have comorbidities,” he told Medscape Medical News.

 

He added that once patients have responded to several weeks of ketamine treatments, efforts are made to help them shift to other forms of management.

 

 

 

“For those patients who do well following a series of four to six ketamine infusions, we initially try and keep them well using a strategy that does not involve repeated use of ketamine,” said Wilkinson.

 

 

 

Concerns Remain

Despite the encouraging improvements in depression that have been reported, the increased popularity of ketamine without long-term safety or efficacy data has raised considerable concerns, as reflected in aconsensus statement issued by an American Psychiatric Association Task Force in 2017.

 

Wilkinson said he shares the task force’s concerns.

 

“Ketamine has tremendous potential, but this needs to be tempered with the potential risks. There needs to be a higher level of regulation than currently exists,” he said.

 

“Ketamine is very safe in the short term, but we need better long-term data, because the risks of long-term adverse effects with repeated use are not theoretical,” Wilkinson added.

 

“We know that too much ketamine is not good for the brain or bladder. We just don’t know how much is too much,” he said.

 

Dr Niciu has disclosed no relevant financial relationships. The senior author of the study is a coinventor on a patent for the use of ketamine and its metabolites in the treatment of major depression. Although he assigned his rights in the patent to the US Government, he will share a percentage of any royalties that may be received. Wilkinson has received funding, administered through Yale University, from Janssen to conduct clinical trials with esketamine. He has also received consulting fees of less than $5000 from Janssen.

 

Anxiety and Depression Association of America (ADAA) Conference 2018. Session 341R, presented April 7, 2018.

 

 

CADSS-test-for-PTSD  <<Clinician-Administered Dissociative States Scale (CADSS)  A test to see how dissociated an individual is – the more the better!

 

Do the dissociative side effects of ketamine mediate its antidepressant effects?

Abstract

Background

The N-methyl-d-aspartate receptor antagonist ketamine has rapid antidepressant effects in major depression. Psychotomimetic symptoms, dissociation and hemodynamic changes are known side effects of ketamine, but it is unclear if these side effects relate to its antidepressant efficacy.

Methods

Data from 108 treatment-resistant inpatients meeting criteria for major depressive disorder and bipolar disorder who received a single subanesthetic ketamine infusion were analyzed. Pearson correlations were performed to examine potential associations between rapid changes in dissociation and psychotomimesis with the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS), respectively, manic symptoms with Young Mania Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item Hamilton Depression Rating scale (HDRS) at 40 and 230 min and Days 1 and 7.

Results

Pearson correlations showed significant association between increased CADSS score at 40 min and percent improvement with ketamine in HDRS at 230 min (r=−0.35, p=0.007) and Day 7 (r=−0.41, p=0.01). Changes in YMRS or BPRS Positive Symptom score at 40 min were not significantly correlated with percent HDRS improvement at any time point with ketamine. Changes in systolic blood pressure, diastolic blood pressure, and pulse were also not significantly related to HDRS change.

Limitations

Secondary data analysis, combined diagnostic groups, potential unblinding.

Conclusions

Among the examined mediators of ketamine׳s antidepressant response, only dissociative side effects predicted a more robust and sustained antidepressant. Prospective, mechanistic investigations are critically needed to understand why intra-infusion dissociation correlates with a more robust antidepressant efficacy of ketamine.

Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression

Highlights

  • Intra-infusion dissociation is associated with antidepressant response to ketamine.
  • Antidepressant response may be uniquely related to dissociative symptom clusters.
  • Depersonalization was globally associated with antidepressant response.
  • Derealization was discriminately associated with antidepressant response.

Abstract

Background

Ketamine induces rapid and robust antidepressant effects, and many patients also describe dissociation, which is associated with antidepressant response. This follow-up study investigated whether antidepressant efficacy is uniquely related to dissociative symptom clusters.

Methods

Treatment-resistant patients with major depressive disorder (MDD) or bipolar disorder (BD) (n = 126) drawn from three studies received a single subanesthetic (0.5 mg/kg) ketamine infusion. Dissociative effects were measured using the Clinician-Administered Dissociative States Scale (CADSS). Antidepressant response was measured using the 17-item Hamilton Depression Rating Scale (HAM-D). A confirmatory factor analysis established the validity of CADSS subscales (derealization, depersonalization, amnesia), and a general linear model with repeated measures was fitted to test whether subscale scores were associated with antidepressant response.

Results

Factor validity was supported, with a root mean square error of approximation of .06, a comparative fit index of .97, and a Tucker-Lewis index of .96. Across all studies and timepoints, the depersonalization subscale was positively related to HAM-D percent change. A significant effect of derealization on HAM-D percent change was observed at one timepoint (Day 7) in one study. The amnesia subscale was unrelated to HAM-D percent change.

Limitations

Possible inadequate blinding; combined MDD/BD datasets might have underrepresented ketamine’s antidepressant efficacy; the possibility of Type I errors in secondary analyses.

Conclusions

From a psychometric perspective, researchers may elect to administer only the CADSS depersonalization subscale, given that it was most closely related to antidepressant response. From a neurobiological perspective, mechanistic similarities may exist between ketamine-induced depersonalization and antidepressant response, although off-target effects cannot be excluded.

 

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Ketamine for resistant depression: Outstanding promise, outstanding issues.

Outstanding Promise.

Ketamine has been around for many years, firstly as a dissociative anaesthetic and then as a psychedelic drug. But it might become best known for it’s powerful antidepressant properties (Berman et al 2000Zarate et al 2006). Compared to existing antidepressants, which take around 2 weeks to work, ketamine exerts a large antidepressant effect on the first day of treatment.

depression ketamine murrough

Figure 1: The antidepressant effect of ketamine over 6 treatment sessions. The improvement on day 1 (measured using the MADRAS scale) was predictive of the response achieved following the sixth treatment session.

The robust antidepressant effect of ketamine also occurs in patients who have not found relief with existing drugs or with ECT. In the latest study to be reported, 24 patients with treatment-resistant depression underwent up to 6 sessions of intravenous ketamine (0.5mg/Kg in 40 mins) over ~2 weeks. Over 70% of patients responded to ketamine, and the overall reduction in depression was large and rapid (Murrough et al 2013) (Figure 1).

Outstanding Issues.

To date a major issue has been the lack of persistence of the antidepressant effect. In previous studies, involving a single ketamine treatment, depression returned within one week of the session or less. In the study by Murrough et al, this was extended to an average of 18 days. This is an improvement, but further work will be needed to solve the problem of the relatively short-lived antidepressant effect of ketamine.

An understanding of the mechanism by which ketamine alleviates depression may be necessary if we are to extend the duration of it’s beneficial effects. Pre-clinical work suggests that ketamine boosts the health and integrity of synapses and neuronal networks. Much of the action is believed to take place within dendritic spines, and involves local protein synthesis (Duman et al 2012) (Figure2).

ketamine mechanism
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Figure 2: The antidepressant effects of ketamine may depend upon activation of mTOR and local protein synthesis in dendritic spines.

Two molecules of relevance are mTOR and GSK-3. Ketamine enhances local protein synthesis by activating mTOR and by inhibiting GSK-3. [GSK-3 inhibits mTOR]. A drug, such as lithium, which inhibits GSK-3 might enhance the antidepressant effect of ketamine. This has now been demonstrated in pre-clinical studies (Liu et al 2013). The clinical question, which will now be addressed in trials is whether lithium treatment extends and enhances the antidepressant effects of ketamine. Lithium has been used for treatment-resistant depression for many years, and has a good evidence base (Bauer et al 2010) so that the combination of ketamine and lithium presents as an interesting and relatively straightforward strategy for stubborn depression.

However it is somewhat odd that the proposed mechanism for ketamine involves new protein synthesis and synaptogenesis (which take time, and are sustained) whereas the clinical effects of ketamine are very rapid (and transient). Other mechanisms may have more explanatory power. For instance a recent fMRI study showed that ketamine decreased the connectivity of limbic and prefrontal regions which are known to be overactive in depression (Scheidegger et al 2012). More provocatively, it appears that the antidepressant effect of ketamine depends upon the extent of the acute psychological reaction produced by the drug. Although the dissociative/psychedelic properties of ketamine are sometimes regarded as unwanted “side-effects”, a recent paper showed that the acute psychedelic and subsequent antidepressant effects are related (Sos et al 2013).

 2013;34(4):287-93.

Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression.

Abstract

OBJECTIVES:

Ketamine and other NMDA (N-methyl-D-aspartate) antagonists produce fast-acting antidepressant-like effects, although the underlying mechanism is unclear. Furthermore, high affinity NMDA antagonists such as ketamine are associated with psychotomimetic effects. To date the link between the antidepressant and psychotomimetic effects of ketamine has not been explored. We examined the relationship between the antidepressant and psychotomimetic effects of a single ketamine infusion in subjects diagnosed with major depressive disorder.

METHODS:

In a double-blind, cross-over, placebo-controlled, two weeks clinical trial we studied the effects of ketamine (0.54 mg/kg within 30 min) in a group of 27 hospitalized depressive patients.

RESULTS:

Higher intensity of psychotomimetic symptoms, measured using BPRS, during ketamine administration correlated with alleviation in mood ratings during the following week with maximum on day seven. Ketamine was superior to placebo in all visits (day 1, 4, and 7) assessed by MADRS with effect size (Cohen´s d) of 0.62, 0.57, and 0.44 respectively. There was no significant correlation between ketamine and nor-ketamine plasma levels and MADRS score change at any study time point.

CONCLUSION:

The substantial relationship between ketamine’s antidepressant and psychotomimetic effects was found. This relationship could be mediated by the initial steps of ketamine’s action, trough NMDA receptors, shared by both ketamine’s clinical effects.

GSK-3 Inhibition Potentiates the Synaptogenic and Antidepressant-Like Effects of Subthreshold Doses of Ketamine

Lithium’s Emerging Role in the Treatment of refractory major depression episodes – augmentation of antidepressants

Subanesthetic ketamine decreases the incentive-motivational value of reward-related cues.

The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers.

Signaling Pathways Underlying the Rapid Antidepressant Actions of Ketamine

 

Cognitive disorders: the role of dendritic spines.

Cognitive disorders: the role of dendritic spines.

www.paulmorrison.org/cognitive-disorders-the-role-of-dendritic-spines/

Neuronal plasticity:

A major contribution of neuroscience to the humanities is the knowledge that the structure of the brain is moulded by the experiences the mind goes through – the phenomenon known as plasticity. It means that the circuits of the brain are sculpted by habitat, schooling, language, relationships, and culture, as well as by the unfolding genetic programme. The action occurs below the micrometre scale – at synapses (the points of connection between neurons) – and involves the exquisite choreography of a number of molecular machines. These molecular processes are so fundamental for cognition that their failure (whether driven by gene mutation or by harsh environments) results in neuropsychological disability. A major locus of plasticity (and hence, cognitive disability) is the dendritic spine.

pyramidal neuron

The dendrites of pyramidal neurons express thousands of dendritic spines. P=pyramidal neuron.

Principal neurons in the brain, such as cortical pyramidal neurons, express tens of thousands of small protruberances on their dendritic trees. These structures (dendritic spines) receive excitatory information from other neurons, and are highly dynamic. They can adjust their responsiveness to glutamate (the major excitatory neurotransmitter), becoming stronger (potentiation) or weaker (depression), as local circumstances dictate. This strengthening (LTP) or weakening (LTD) can be transient, or persist over long periods and as such, serves as an ideal substrate for learning and memory at synapses and in circuits. Potentiated spines increase in size, and express more AMPA glutamate receptors, whilst the opposite pattern occurs in synaptic depression to the extent that spines can be ‘absorbed’ back into the dendritic tree.

Over the course of childhood, dendritic spines (excitatory synapses) increase in number, but their numbers are ‘pruned’ back during adolescence to reach a plateau. Enriched environments have been shown to increase spine density, impoverished environments the opposite. In common psychiatric disorders, spine density is altered. For example, the most robust histological finding in schizophrenia is a reduction of spine density in the frontal cortex, auditory cortex and the hippocampus. In major depression, spines (and dendrites) are lost in the hippocampus. In autism, spine density actually increases. Finally, in Alzheimer’s and other dementias there is a catastrophic, and progressive loss of cortical and sub-cortical spines.

REGULATION OF THE SPINE:

The molecular biology of dendritic spines involves hundreds of proteins, but the outlines are now reasonably well understood. Scaffolding proteins [such as PSD95, shank(s), AKAP, stargazin and homer(s)] provide structural support and provide orientatation for membrane bound receptors, ion-channels and their downstream signalling pathways. The scaffold (post-synaptic density), facilitates effective signalling by ensuring that the correct protein partners are in close apposition. The scaffold is also tethered to proteins which bridge the synaptic cleft (cell adhesion molecules) and to bundles of actin filaments which provide the structure and force for spine enlargement (and retraction).

dendritic spine

Spine plasticity is fundamental for learning and memory. The shuttling of AMPA receptors underlies early phase plasticity. Modification of the actin cytoskeleton and local protein synthesis underlie long term plastic changes.

There is a constant remodelling of the actin cytoskeleton within the spine in response to synaptic and network signalling. Remodelling is via small, cytoplasmic G-proteins from the RHOfamily. Some family members promote the growth and stabilisation of actin filaments, whereas others promote actin disassembly. Mutations in the proteins which regulate actin dynamics are a cause of learning disability. Finally local protein synthesis (and degradation) occurs within dendritic spines, is tightly controlled and is essential for plasticity. Abnormalities in local protein synthesis within the spine underlie learning disability syndromes such as fragile X, neurofibromatosis and tuberous sclerosis.

Spine pathology:

Recent years have seen glutamate synapses move to centre stage in neuropsychiatry. This is not surprising given the role of pyramidal neurons (glutamate containing neurons) in information processing, and the role of glutamate transmission in learning and memory [see link]. But it is remarkable that so many psychological and cognitive disorders appear to ‘coalesce’ at dendritic spines.

The enclosed vector-graphic image [click here] highlights a selection of some of the proteins which are now known to be involved in autism, learning disability and schizoprenia.

Research will continue to decipher the complexity (and beauty) of the dendritic spine, but potential treatments are starting to emerge for disorders like fragile X, (which until recently were thought to be not amenable for drug treatment, as was the case for schizophrenia until the 1950s). Molecular neuroscientists will, almost certainly, continue to uncover more treatment targets. The task for psychiatry, as ever, is to keep abreast of neuroscience in all it’s complexity (and beauty).

Glutamate & GABA for psychiatrists

Rapid Dissemination of Information
Glutamate and GABA are the archetypal ‘fast’ transmitters. If a neuron in the brain ‘wishes’ to communicate rapidly with another cell, the chances are that it will utilise glutamate or GABA. Of course, glutamate neurons exert an excitatory influence on the cells they contact, whereas GABA, at least on first glance, is inhibitory.

Fast transmitters bind to receptors on membrane-spanning ion channels. An ion-channel is in constant flux between various conformations: e.g. open, closed, desensitised. Binding of fast transmitter ‘causes’ the ion channel to snap open for brief periods, and ions rush down their concentration gradients causing an abrupt, short-lived, change in the local membrane potential of the post-synaptic cell (Figure 1). From start to finish the whole process is over within tens of milliseconds, and constitutes a discrete electrical signal (termed an excitatory or inhibitory post-synaptic potential; EPSP, IPSP).

nmda receptor

Figure 1. The NMDA Receptor mediates an EPSP.

Neurotransmission v neuromodulation
Fast transmission, as a concept, pre-supposes slow transmission. The classical slow transmitters are the monoamines, e.g. noradrenaline and dopamine. These substances are used as transmitters by neurons within specific brainstem nuclei, whose axons project to numerous subcortical structures and large areas of cortex. There are relatively few monoamine neurons (tens of thousands), but their projections show massive arborisation within the ‘higher centres’ and the limbic system. Anatomically, glutamate and GABA signalling is characterised by point-to-point communication between narrowly separated (and tethered) pre-synaptic and post-synaptic elements, whereas for monoamine systems, the release sites (boutons) and post-synaptic receptors are not necessarily in close proximity. In contrast to glutamate and GABA, which convey a fast, discrete, short-lived electrical signal, monoamines evoke slower-onset, diffuse, longer-duration biochemical changes in their target neurons. Monoamine systems are not optimised for the rapid dissemination of specific information, but instead for modulating those neurons that are.

Ensemble formation and Gestalts
Pyramidal neurons (the principal output neuron of the hippocampus and cortex) use glutamate as a transmitter to communicate rapidly with neurons in ‘lower centres’ such as the striatum, thalamus, pontine nuclei and the cord although most communication is with other pyramidal neurons. Pyramidal neurons organise themselves into ensembles. This process, in which pyramidal neurons fire in synchrony for brief periods of time is thought to be essential for object perception and for movement, speech and thinking.

Consider a pyramidal neuron ‘sitting’ at resting-membrane-potential (-70mV). It receives tens of thousands of excitatory (glutamate) inputs on its dendritic spines, (dynamic structures that are moulded by experience over a lifetime). A single excitatory input (by itself) has little overall impact on the pyramidal neuron. But when numerous EPSP’s from a multitude of inputs arrive ‘synchronously’, the depolarisation may be sufficient for the pyramidal neuron to fire an action potential (AP). In short, the pyramidal neuron is recruited (by the ensemble) into joining the ensemble.

It can be grasped that for AP firing to occur in a pyramidal neuron, there has to be a convergence of excitatory information from numerous sources. Excitatory inputs come from various thalamic nuclei and from stellate cells (in primary sensory cortices), although the overwhelming majority come from other pyramidal neurons. Regardless of the source, timing is key. In order to generate enough depolarisation to trigger an AP, inputs must arrive (and summate) within the same narrow time window (of the order of milliseconds).

Precise Timing and cortical dynamics
The output of a pyramidal neuron (AP spiking) is finely controlled. Precise timing is so fundamental for cortical processing that various auxiliary neurons appear to be tasked with a pacemaker role. These neurons utilise GABA as a transmitter. Classical neuroscience conceptualised GABA containing neurons as nothing more than inhibitory interneurons – this is no longer tenable. There are various populations of GABA containing neuron, which have been classified according to their morphology, their location in the cortex, which proteins they use to sequester calcium, and their electrophysiological properties. Some are even excitatory. For simplicity, we shall restrict ourselves to a simple classification based upon where the GABA neuron contacts the pyramidal neuron (Figure 2).

glutamate and gaba neurons

Figure 2. A pyramidal neuron receives inhibitory GABA-ergic input to its dendrites. GABA pacemakers synapse on the soma and axon initial segment.

 

Contacts formed with the dendrites of pyramidal neurons function as inhibitory interneurons in the classical sense (i.e. they oppose excitatory drive), whereas GABA neurons targeting the soma or the proximal axon (of the pyramidal neuron) function as pacemakers. We can consider how these GABA pacemaker neurons are optimised for their task. Firstly they have very fast dynamics, swifter for example than the pyramidal neurons that they make contact with. Secondly, they provide a very strong and reliable signal to the pyramidal neuron by engulfing the soma or the proximal axon with numerous terminals. A strong, brief, recurrent signal to the soma and proximal axon creates a series of time windows, which determine precisely when the pyramidal neuron fires. Thirdly, individual pacemaker neurons make contact with numerous local pyramidal neurons. And finally, groups of pacemaker neurons are connected by electrical synapses (gap junctions) so that they can function as an interconnected single entity, a syncytium. For completion, pyramidal neurons make strong, reliable synapses (excitatory) with pacemaker neurons.

It is readily apparent that the interconnectivity of pyramidal neurons and GABA interneurons favours the emergence of oscillations, with successive, precisely timed periods of integration followed by periods of AP discharge. Experiments have shown that the population of neurons in an active ensemble generate the rhythm, whilst the rhythm puts precise constraints upon when an individual neuron can fire.

Systems and levels
For slow, diffuse modulators such as noradrenaline, it makes sense to talk of a system. To recap, noradrenaline [NA] is synthesized by no more than tens of thousands of neurons, confined to discrete nuclei within the brainstem, and is ‘sprayed’ from en-passant boutons over large territories of CNS tissue, in a hormone-like manner. Crucially, the release patterns of noradrenaline [and other neuromodulators] can be clearly mapped onto distinct behavioural states, the most marked differences arising in the sleep-state [noradrenaline – ‘off’] versus the waking-state [noradrenaline – ‘on’]. Since the extracellular concentrations of noradrenaline [and other neuromodulators] can inform directly about higher brain/mind levels, the idea of a noradrenergic system has utility.

Glutamate and GABA are too ubiquitous as fast point-to-point transmitters for the term ‘system’ to be applicable in the same way. Particular patterns of behaviour cannot be mapped onto the release of GABA or glutamate at a specific locus. All we can say is that neurons in an ensemble use glutamate and GABA to communicate with each other. Whereas transient fluctuations in the extracellular concentrations of GABA/glutamate do not reveal anything about behaviour, the dynamics of neuronal ensembles correspond with distinct behavioural states. Again the sleep wake-cycle is illustrative. Oscillatory activity generated by the ensemble can be mapped unambiguously onto the sleep-state and the waking-state.

Learning & Memory
In the 1970s it became clear that excitatory connections onto pyramidal neurons could be made stronger, if they were subjected to particular patterns of input. This was the first experimental support for an idea that can be traced back to Ramon y Cajal – the idea that synapses are modifiable (plastic) and that such plasticity might serve as the physical basis of memory.

There are various forms of plasticity, but the most widely studied is NMDA-dependent long-term potentiation (LTP). In the early 1980’s, researchers based in Bristol showed that NMDA receptor antagonists could block the initiation of LTP [and subsequent behavioural experiments, (most famously, by Richard Morris in Edinburgh) showed that such drugs could inhibit new learning].

NMDA receptor channels are found at the heads of dendritic spines, adjacent to the glutamate terminal. AMPA receptor channels are found in the same locale. When activated, both receptor channels produce an excitatory-post-synaptic-potential (EPSP). In the case of the AMPA receptor, the EPSP is mediated by sodium ions flowing into the spine. For NMDA receptors, the EPSP is mediated by a combination of sodium and calcium ions. [It is the calcium signal that initiates LTP (Figure 3). Early-phase LTP is mediated by phosphorylation of AMPA receptors (increasing their conductance) and by insertion of new AMPA receptors into the post-synaptic membrane].

long term potentiation

Long Term Potentiation (LTP) is induced by NMDA receptor activation. The mechanism of early-phase LTP involves the enhancement of AMPA receptor conductances and insertion of new AMPA receptors into the post-synaptic membrane.

AMPA and NMDA receptor channels differ in one other key property. The NMDA channel is voltage-dependent. At membrane potentials less than -50mV, the NMDA channel remains closed, even if glutamate is bound to the receptor. For the NMDA channel to snap open, the membrane potential must be already depolarised to at least -30mV. So two conditions are necessary for NMDA conductance; binding of glutamate and membrane depolarisation. For this reason, the NMDA receptor is said to be a coincidence detector (or in engineering terms, an AND gate).

Sufficient post-synaptic depolarisation can occur from backward-propagating action potentials (APs) or from temporally or spatially summated excitatory input to a dendritic branch. Research in the last decade has revealed that the timing of pre-synaptic activity (glutamate release) and of post-synaptic activity (post-synaptic-depolarisation) is critical in determining whether synaptic strength will be altered. Pre and post synaptic ‘events’ must occur within approximately 20 milliseconds, otherwise synaptic strength remains unchanged. This form of plasticity, known as Spike-Timing-Dependent-Plasticity (SDTP), is likely to become increasingly relevant as we begin to conceptualise ‘micro-circuit’ abnormalities in major neurodevelopmental disorders. Two final points about SDTP will be made here. Plasticity is bidirectional (potentiation or depression) depending on the order of pre and post-synaptic events. And conventional modulators such as dopamine can impact upon the timing rules and alter the direction of the plasticity, (LTP or LTD).

Some Psychiatry: The K-Hole and beyond
Ketamine, a drug that has attracted the attention of psychiatrists in the past few decades, ‘blocks’ the NMDA channel. It has been used as a model psychosis, and latterly has been demonstrated to have acute anti-depressant properties. (It certainly impairs new learning, as would be expected).

Downstream of NMDA blockade, there is no clear consensus as to how ketamine produces a psychosis. Counter-intuitively (for a glutamate antagonist), ketamine increases the excitability (spiking) of pyramidal neurons. Ketamine also increases the power of gamma band (~40 Hz oscillations) and some have proposed that ‘kernels’ of ‘abnormal’ gamma underlie the psychotic-like effect.

But the behavioural pharmacology of ketamine is far from straightforward. Rating-scales used in schizophrenia research, are probably not ideal for capturing the nuances of the drug. Those who have taken a more phenomenological approach [in the sense of ‘bracketing-out’ existing assumptions, whilst focussing on clear descriptions] have identified a much richer and more complex behavioural psychopharmacology, which includes euphoria, near-death experiences, the cessation of time, the dissolution of the ego, and the experience of being immersed in fractal geometries or boundless oneness (Jansen K, Ketamine: Dreams & Realities 2000).

Close observation reveals the dose-dependent emergence of an oneroid (dream-like) state, and other catatonic features (ambitendency, posturing) but not a classic paranoid psychosis. Researchers have also tended to assume that ketamine can ‘cause’ negative symptoms, but reports of euphoria, terror and awe are inconsistent with this categorisation. Motor output (which includes speech of course) is certainly restricted following ketamine, but because the concurrent inner world is a kaleidoscope of strange, mystical and fantastic experiences with extremes of emotion, the overall picture is far removed from the negative syndrome.

Nevertheless, ketamine is frequently championed as the most convincing drug-model of schizophrenia because it can induce negative symptoms, on a rating scale. The irony perhaps is that the ketamine experience might actually be more schizophrenia-like than many of its proponents have suggested. Ketamine elicits phenomena, which are now very rarely encountered in psychiatric clinics, given the modern-day domination of the softer, paranoid form of the illness.

Update

Paul Janssen’s genius was in predicting that a drug which blocked the effects of amphetamine in animals, would be an effective treatment for those cases of schizophrenia that resembled an amphetamine psychosis (characterised by agitation, hallucinations and delusions)[link]. That drug was haloperidol, and that class of drug (D2 dopamine receptor antagonists) changed the landscape of psychiatry.

Janssen’s logic would also suggest that a drug which inhibited the effects of ketamine in animals, would be an effective treatment for those cases of schizophrenia which resemble ketamine-elicited psychopathology (characterised by bizarre, inaccessible dream-like states, and psychotic motor phenomena. i.e. cases where ECT becomes a sensible option). A pharmacological antagonist of ketamine (in animals) proved to be ineffective against human paranoid schizophrenia. Perhaps this could have been predicted, by closer attention to the phenomenology of ketamine. The question now is whether ‘The Lilly compound‘ has efficacy against non-paranoid schizophrenia?

Natural antidepressants & new brain cells

New Brain Cells

In the last decade it has become clear that new cells can form in the adult brain. This happens in a region known as the hippocampal complex. The hippocampal complex is found deep inside either temple and is crucial for memory and emotion. The hippocampal complex inhibits the human stress response, but can itself be damaged by persistent stress, leading to a vicious cycle in which the stress response is amplified further and depression ensues.

hippocampus from nieuwenhuys et al

The hippocampal complex is found in the temporal lobe, and has a crucial role in regulating the stress response.

Experimental work suggests that neurogenesis (the birth of new neurons) in the hippocampal complex is vital for the action of conventional antidepressant drugs. Exercise and enriched environments also promote neurogenesis, whilst stress has the opposite effect.The current picture is that hippocampal health (including the birth of new neurons) is essential for protecting the organism against the effects of stress, so that if hippocampal functioning is compromised, anxiety and depression can emerge.

 

Natural Antidepressants

There has been recent interest in the antidepressant properties of a natural molecule called curcumin. This substance is found in the herb turmeric. As well as a foodstuff, turmeric has been used for centuries in traditional Indian medicine (Ayurveda). In pre-clinical studies, curcumin exhibited clear antidepressant effects.

curcumin

Research has focused on the mechanism of action of curcumin. Remarkably it appears that curcumin can also increase the birth of new neurons in the hippocampal complex. This is an intriguing finding which hints at the possibility of a new class of antidepressant drug.

A new paper from researchers at King’s College London provides an excellent summary of work in this area. The full paper can be read here.

 

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Stopping Alcohol Abuse with Ketamine

ReachMD Ketmaine on Roundtable talk

ketamine-to-treat-alcoholism transcript

Stopping Alcohol Abuse with Ketamine   << Article Link

A currently ongoing study based at University College London (UCL) involves giving a dose of ketamine to alcohol abusers. Yes, you read that correctly. Ketamine is a legal tranquilizer, used mainly on small animals by veterinarians. However, ‘Special K’ doubles as a recreational drug, found most often at dance parties and nightclubs. So how the heck does ketamine stop alcohol abuse? The answer is by manipulating alcohol-associated memories.

Let’s start over.

ketamine-picture

Certain things make drinkers want to drink. Ask anyone who consumes alcohol often, and they’ll tell you it’s true. Maybe the smell of alcohol triggers the desire to drink. Maybe it’s a certain place, or some classic rock song. When this happens, the drinker’s memories of alcohol giving pleasure are recalled, and his or her brain wants that alcohol-induced pleasure again. This is the precursor to alcoholism, wherein the brain can’t function without alcohol.

Cravings are essentially fond memories. You are recalling the pleasure of something and desiring it again. During this memory recall, “…the neural connections that encode [the memory] are temporarily destabilized, meaning that our recollection can be slightly altered before it goes back into storage,” as written in The Guardian, linked above.

Ketamine causes memory loss and/or disruption, by blocking a receptor in the brain called NMDA. This particular receptor is partly responsible for our ability to form memories. The UCL research team believes they can use this effect of ketamine to ‘erase’ the memories associated with craving alcohol. “There is evidence that it could be useful as a treatment for alcoholism,” said lead researcher Ravi Das.

The Library Book Metaphor

Every time you access a memory, you are basically removing it from your mental library. In a real library, a book can be removed and read, like a memory can, but it also becomes vulnerable. The book borrower could rip a page out, cross out some text, or even damage the book. The same thing goes for memories. This is why we give slightly different accounts of our past each time we do so.

Because ketamine disrupts the memory-formation process, the idea of the UCL study is to trigger alcohol cravings in participants, and then give them ketamine. The hope is to weaken the alcohol-related memories, ultimately to the point of non-existence.

A dose of ketamine administered at the time of alcohol-related memory recall, the researchers hope, will make it so you lose the book of alcohol-craving from your mental library. The ‘temporary destabilization’ of our memories, when recalled, acts as the window of opportunity for ketamine to work. The ultimate goal is to eliminate the triggers for craving a drink.

The UCL Study

The research team consists of psychologists from University of Exeter, Imperial College London, and UCL. Participants must consume at least forty drinks per week, drinking four or more days per week. This qualifies them as heavy drinkers. However, participants cannot be clinical alcoholics. Anyone with diagnosable alcohol dependence would be excluded. They are aiming for 90 people to participate, and at the time of a July 2016 publication, over 50 people were already in.

Apparently no further details have been published yet about whether or not the quota has been met. Some details on what the study involves have been published, and as of the time of this writing, a flyer advertising the study is still online. So far, here’s what we know the study entails:

The psychologists intentionally trigger the craving for alcohol in the participants. A glass of beer is placed directly in front of each person. This is a surefire trigger – no scientific explanation needed. The details of what happens next are being withheld by the team. However, according the Guardian, “They will then disrupt the memory, by surprising the participant (the team is not disclosing the exact details as this could bias the results).”

The ketamine comes next. After the memory is triggered and disrupted, each participant is either given “a ketamine infusion, with a concentration equivalent to a high recreational dose, or a placebo.” The team then stays in touch with all 90 people for one full year after the ketamine dose, to see how their drinking habits have changed.

Short-term Results are Promising

One participant, who already received the ketamine dose, claims that it worked. According to the Guardian article, 31-year-old Nikki, a consultant in London, took part in the study when she realized she was drinking heavily. She was even drinking more than she wanted to. “It’s just in the culture. That’s what all my friends are like… everyone drinks to excess,” she said before the study.

After her alcohol craving was triggered and her memory was manipulated, Nikki was given her ketamine dose. She described the experience as overwhelming and intense, but not unpleasant. “It was quite psychedelic. I felt untethered from my body,” she said.

One week later, Nikki reported an “incredible positive mood,” and said she was much more aware of her decisions regarding drinking. She didn’t say she gave up alcohol completely. However, she did praise the study. “In the past, there were occasions where I would be drinking and I’d be on autopilot: ‘Let’s get another drink’,” said Nikki.

Although one week is only 1/52nd of a year, Nikki’s story proves as a promising example of how a ketamine dose could prevent heavy drinking.

Similar Approaches to Different Problems

Using one drug to fight the abuse of another drug is not unheard of. Actually, two years ago, Merel Kindt and Marieke Soeter of University of Amsterdam performed a study that used a beta-blocker to get rid of arachnophobia. Beta-blockers are used primarily for cardiac care. The particular one used in the study, propranolol, treats high blood pressure, and is also used to reduce performance anxiety.

Fifteen participants with diagnosed arachnophobia, a fear of spiders, were shown a giant tarantula, and told they had to touch it. Then they were each given a dose of propranolol. The arachnophobia was gone for good.

According to the article linked above, “They erased their spider fear memories and then rewrote them with one of triumph — touching the tarantula a week after their treatment. When they returned to her lab three months and a year later, the effects stuck.”

Michael Saladin is attempting to end tobacco addiction with a similar approach. He is a professor at the Medical University of South Carolina, and he believes smoking addictions can be ended by getting rid of the cues (triggers) that make addicts smoke.

“There is a vast animal research literature that suggests memories can be manipulated following reactivation,” Saladin said. “I am convinced that there is sufficient evidence to believe that memory reconsolidation can be harnessed for clinical purposes.”

Memory Reconsolidation

The process being utilized in the UCL study, as well as in both studies mentioned above, is known as memory reconsolidation. The entire concept is relatively new. Essentially, the idea is to replace the bad memories associated with certain things with good memories, feelings of accomplishment and healthy pride. In the case of resisting alcohol, the already-consolidated memories of drinking will be replaced with new memories of feeling proud of not drinking. The ketamine allows this process to occur.

This may seem futuristic to you, and frankly it is. Scientists discover new information every day, and in the age of the microchip, our limits are becoming harder to see. New methods for how we do just about everything are being found. Yet when the use of illegal drugs, (ketamine is illegal to possess and is not a prescribed drug), becomes one of the methods that scientists discover, there tends to be a lot of pushback.

The scientists wish people would stop resisting.

Just because something is illegal and/or looked down on by society doesn’t mean that something isn’t effective in another way. We are seeing this nationwide with marijuana.

The Pushback

Lead researcher Das spoke to this resistance the public has for illegal/illicit drugs being used as medicines: “There’s just the general social attitude that everything that’s illegal is terrible. There will obviously be that kind of narrow-sighted pushback, but if it’s safe and effective enough it should be recommended.”

Das isn’t implying that ketamine is safe to use for anyone who wants to fix a bad memory. What he’s implying is that in a controlled, medical environment, a one-time dose of ketamine could help heavy drinkers relax on the booze.

Quoted in the Guardian article, Andrew Misell is a spokesman for Alcohol Concern, a non-profit charity working to reduce alcohol harm in the UK. Speaking about the UCL study in particular, he said, “The researchers have quite rightly highlighted what a lot of people in recovery from alcohol problems know from experience, namely that cues or triggers like the smell of beer can cause a relapse even after long periods of abstinence. Any work looking at how people can overcome these pitfalls is going to be useful.”

Misell added that he knows ketamine-based therapy has risks. What Misell didn’t add is that alcohol abuse has much more inherent risk than drug-based therapy. Not to mention, ketamine itself is significantly safer, and much less abused, than xanax, the number one drug used in all of psychotherapy.

Why the Pushback?

Medicine is medicine. Unless you the reader are a scientist or a doctor, you and I have no influence on what becomes medicine. If a one-time dose of ketamine can prevent alcoholism, why would anyone resist? Xanax is the most prescribed drug in all of psychotherapy, yet people abuse it WAY more often than ketamine. The NY Post published an article just last year explaining this, going so far as to say that xanax is ruining lives.

OxyContin, a drug used rather commonly for chronic pain, legal with a prescription, ends the lives of 100,000 people every single year. So why the pushback for ketamine?

In Conclusion

Drug/alcohol abuse is a horrible thing. People are dying in mass numbers from drug/alcohol abuse, and not just in America. This author does not condone the abuse of alcohol, nor does this author condone the use of illicit drugs. However, as this author wrote prior, what becomes a medicine is not a decision for anyone but scientists and doctors. If yours truly was a heavy drinker, and a doctor told me that habit could be stripped away with a one-time dose of ketamine, believe that no more questions would be asked.

One can only wait for the final results from the UCL study to see how many more participants turn out like Nikki. If and when the study proves effective for more and more people, we may begin to see a radical change in the way we fight addiction. It may seem like fighting fire with fire, but sometimes it works. Brushfires that spread rapidly are sometimes stopped by deliberately burning a section of earth where the fire is headed. Maybe ketamine is that deliberate burn in the realm of alcohol addiction

Tip sheets:

Prof Evgeny Krupitsky – Ketamine Psychotherapy For Heroin Addiction: Immediate Effects and Two-Year Follow- up

 1997 Apr-Jun;29(2):165-83.

Ketamine psychedelic therapy (KPT): a review of the results of ten years of research.

Abstract

Ketamine is a prescription drug used for general anesthesia. In subanesthetic doses, it induces profound psychedelic experiences and hallucinations. The subanesthetic effect of ketamine was the hypothesized therapeutic mechanism in the authors’ use of ketamine-assisted psychotherapy for alcoholism. The results of a controlled clinical trial demonstrated a considerable increase in efficacy of the authors’ standard alcoholism treatment when supplemented by ketamine psychedelic therapy (KPT). Total abstinence for more than one year was observed in 73 out of 111 (65.8%) alcoholic patients in the KPT group, compared to 24% (24 out of 100 patients) of the conventional treatment control group (p < 0.01). The authors’ studies of the underlying psychological mechanisms of KPT have indicated that ketamine-assisted psychedelic therapy of alcoholic patients induces a harmonization of the Minnesota Multiphasic Personality Inventory (MMPI) personality profile, positive transformation of nonverbalized (mostly unconscious) self-concept and emotional attitudes to various aspects of self and other people, positive changes in life values and purposes, important insights into the meaning of life and an increase in the level of spiritual development. Most importantly, these psychological changes were shown to favor a sober lifestyle. The data from biochemical investigations showed that pharmacological action of KPT affects both monoaminergic and opioidergic neurotransmitter metabolism, i.e., those neurochemical systems which are involved in the pathogenesis of alcohol dependence. The data from EEG computer-assisted analysis demonstrated that ketamine increases theta activity in cerebrocortical regions of alcoholic patients. This is evidence of the reinforcement of limbic cortex interaction during KPT session.

Ketamine is gaining widespread acceptance as a fast and effective treatment for depression. It is so successful that ketamine has been called “the most important discovery in depression research in half a century” says Ronald Duman MD, Professor of Psychiatry at the Yale University School of Medicine. “A single dose of ketamine alleviates depressive symptoms within hours in patients who have failed to respond to two or more conventional antidepressants” he states in a scientific article published in the respected journal Science.

Researchers now believe it can treat more than depression and anxiety. Ketamine has recently generated a lot of interest among psychiatrists and addiction medicine physicians as a potential new and rapidly effective approach to treating struggling with other difficult-to-treat conditions such as substance abuse disorders and alcohol dependence.

“Current treatments benefits for alcoholism are at best modest, about three quarters of people return to drinking after 6 months, so there is a great need for new and more effective therapies” said Dr. Grass, Director of the Ketamine Institute in Pensacola Fl. “Many patients who come to us for ketamine therapy with conditions such as depression, anxiety or PTSD have self-medicated with alcohol or opioids to find relief. Initially, they find that alcohol seems to help their symptoms until it doesn’t anymore and it then become another serious medical issue in their lives” says Dr. Grass.

Can Ketamine Cure Alcoholism or Drug Addiction?

Research studies are currently underway at Yale and Columbia University in the United States and the University of Exeter in the United Kingdom to explore the beneficial effects of ketamine infusions on substance abuse disorders. Ketamine has already been shown to be an effective for depression, something that many people with substance abuse issues encounter as they try to become sober. As an antidepressant, it’s unique in that it acts very quickly, with patients often reporting an improvement in their mood over just one or two days. That could make it ideal for treating active, as well as, recovering alcoholics, who often suffer from depression immediately after quitting.

“This form of therapy is not new, says Dr. Grass. We have known for almost 30 years that ketamine may be effective in dealing with substance abuse issues.” In the 1990’s, Dr. Evgeny Krupitsky published research documenting over 10 years of observations utilizing ketamine for substance abuse disorders. His results suggest that ketamine can be remarkably more effective that current treatment options. Few people with substance abuse disorders can maintain abstinence following therapy with traditional approaches. However, Krupitsky found that as many as 66% remained alcohol free after one years as compared to only 24% with traditional treatment.

In addition, Krupitsky also found that the beneficial effects were dose dependent and that those people who received higher dosages of ketamine did better than those who received lower amounts. Following the study, psychological testing revealed that ketamine treated patients showed improvement on tests such as the Minnesota Multiphasic Personality Inventory (MMPI) personality profile. Changes seen included a positive transformation of self-concept and emotional attitudes, positive changes in life values and purposes. Patients also experienced important insights into the meaning of life and an increase in the level of spiritual development. Most importantly, these psychological changes tend to favor a sober lifestyle.

“We see many patients with depression, anxiety or PTSD who have at one point or another turned to alcohol or other substances to find relief only to become dependent upon these drugs”, says Dr. Grass. “A ketamine infusion, given at the right dose, can be a remarkably effective therapy in reversing these symptoms and alleviating their dependence upon alcohol or opioids. Often after just several ketamine treatments they can stop drinking and have no interest in alcohol or drugs after that.”

Ketamine – It’s Just the Beginning

Although more research is needed to determine exactly why there’s such a strong correlation between ketamine therapy and decreased use of alcohol and opioids, this observation does appear to validate the experiences of many people who have found substances like ketamine be life-changing tools that have helped them lead happier, more fulfilling lives. For many, this therapy has helped them cut back or quit their use of alcohol, opioids or other substances with which they have had a problematic relationship. One day, doctors may use ketamine routinely not only to help severely depressed people, but many who suffer from related conditions such as alcohol and substance abuse issues. “While the science is very promising, ketamine is not to be considered lightly and must be carefully monitored when used. But with the excitement generated by early results, we will have more information soon,” Grass says.


References:

Duman RS, Aghajanian GK, (2012) Synaptic Dysfunction in Depression: Potential Therapeutic Targets. Science. 338(6103):68-72.

Synaptic Dysfunction in Depression Potential Therapeutic Targets

Krupitsky EM, Grinenko AY, (1997) Ketamine Psychedelic Therapy (KPT): A Review of the Results of Ten Years of Research. Journal of Psychoactive Drugs. 29(2):165-83

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ketamine-and-rehab-therapy – Thailand

Ketamine Therapy

One of the most controversial issues surrounding ketamine is that it has been found to be an effective tool in therapy for addiction and depression. Researchers studied the effects of the drug on individuals who suffered severe depression and found that it was effective in relieving both symptoms and increased the effectiveness of psychotherapy. The drug has had interesting and astonishing results when used on patients who suffer from difficult depressive conditions, including bipolar disorder. The fast-acting nature of the drug proved to be the most interesting anti-depressant effect. Typically, anti-depressant medications can take days or weeks to start working which can prove ineffective if someone is suffering from a depression crisis. Administration of ketamine has provided immediate and short-acting results against depression, though it has been found ineffective in the long term.

Ketamine has been used as an alternative drug and alcohol therapy for nearly 30 years. The drug is administered under clinical conditions to individuals who are suffering the effects of chronic addiction and depression and the results have proved to be effective for some people. The drug has been found to only provide positive outcomes after detoxification from other drugs has occurred, and it is combined with effective professional psychotherapy. One study showed that there was a significant increase in the level of anhedonia, depression and anxiety that recovering heroin addicts experienced when they had been through ketamine psychedelic therapy. This is a significant result and such information may increase the use of ketamine as a therapeutic tool.

 

 

Clinical Trial:

https://clinicaltrials.gov/ct2/show/NCT01551329

Detailed Description:

Major depression and alcohol dependence are both within the ten disorders for highest worldwide disease burden as identified by the World Health Organization (WHO), and these disorders frequently co-occur, especially in high-service utilizing patients with severe and persistent mental illness. Currently available treatments are inadequate for both chronic conditions alone, and the inadequacy is even clearer in people meeting criteria for both disorders. Ketamine was first reported as a rapidly-acting antidepressant in 2000 via research occurring at Yale, and, since that time, in several small randomized controlled trials, a single subanesthetic dose of intravenous ketamine has demonstrated efficacy in improving mood in unipolar and bipolar depression within only hours after administration. These effects can last at least a week. Interestingly, ketamine has been demonstrated to produce a more robust effect in treatment-refractory unipolar depressed subjects with a family history of alcoholism relative to similarly difficult-to-treat subjects without a family history of alcohol problems. In addition, recently-detoxified alcoholics have been safely administered subanesthetic doses of ketamine, and, during these infusions, alcoholics (and even those with only a family history of alcoholism) displayed a differential response to ketamine, e.g. blunted psychotic-like and cognitive effects, relative to healthy controls. Therefore, ketamine may reduce depressive symptoms and alcohol consumption compared to placebo in patients with comorbid major depression and current alcohol dependence. Positive results will mark a major advance in the clinical care of those being treated for both conditions and will open the door for further scientific investigations into the clinical neuroscience of these highly comorbid and prevalent conditions.

This is a two phase, double-blind, randomized, placebo-controlled, cross-over, proof-of-concept study designed to determine the effects of a single dose of ketamine, administered IV, on mood and alcohol consumption, in psychotropic medication-free patients meeting DSM-IV-TR criteria for a major depressive episode (MDE) and current alcohol dependence. Participants will be assigned randomly to receive either intravenous ketamine (0.5mg/kg) or saline solution 2 weeks apart in a cross over design. The ketamine dose was based on previous studies in patients with depression and bipolar disorder. A team member experienced with ketamine infusions will administer the study medication over a 40-minute infusion in a blinded fashion at the Biological Studies Unit at the WHVA.

20 depressed alcohol dependent subjects between the ages of 21-65 will be recruited for this study through advertising and the West Haven VA clinics. Subjects will complete an informed consent process and will be thoroughly screened for inclusion and exclusion criteria as described below. Individuals will be given a post consent test to evaluate their understanding of the procedure. For subjects who provide incorrect answers to any of the test items, the research staff will review the correct answers with the subject and show the subject where the correct answers are found in the consent form. Those who get more than 60% of the questions wrong and are still unable to understand the procedure after reviewing it with the research staff will be excluded from the study. They will be referred to appropriate resources for outpatient treatment of their depression and alcoholism. Before start of the study all patients will be free of any psychotropic medications.

Ketamine for cocaine treatment

On the motivational properties of reward cues Individual differences

Subanesthetic ketamine decreases the incentive-motivational value of reward-related cues.

The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers.

Ketamine emerging as top treatment for cocaine dependence

EXPERT ANALYSIS FROM THE ECNP CONGRESS

 

– The prospect on the horizon of two new effective therapies for chronic cocaine dependence – sustained-release dextroamphetamine and subanesthetic ketamine infusions – was among the top developments of the year in addiction medicine, Wim van den Brink, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.Other highlights on his list included:• Studies establishing that comorbid attention-deficit/hyperactivity disorder (ADHD) and substance use disorder now can be treated effectively with either extended-release mixed amphetamine salts or high-dose methylphenidate.

Dr. Wim van den Brink

Dr. Wim van den Brink

• Evidence that the alpha-1 blocker doxazosin is an effective treatment for alcoholism in a specific well-defined subset of patients, opening the door to a personalized medicine approach to this disease.• Release of a puzzling array of conflicting studies on the use of high-dose baclofen for treatment of alcohol dependence. It’s tough to reconcile this mishmash of polar opposite results. And that dictates it’s time to declare a moratorium on the use of this therapy in clinical practice, which in many places is now widespread, said Dr. van den Brink, professor of psychiatry and addiction at the University of Amsterdam and director of the Amsterdam Institute for Addiction Research.

“It’s too strange that we have such conflicting evidence out there. Too many people are prescribing crazy-high doses of baclofen with no strong supporting evidence,” Dr. van den Brink said.

Cocaine dependence

Dr. van den Brink was a coinvestigator in a Dutch multicenter randomized, double-blind, placebo-controlled trial of multitreatment-refractory comorbid cocaine dependence in 73 heroin-dependent patients in heroin-assisted treatment. Patients assigned to 60 mg/day of sustained-release dextroamphetamine, in addition to the background methadone and diacetylmorphine all participants were on for their heroin dependence, had significantly fewer days of cocaine use in the 12-week study: a mean of 44.9 days, compared with 60.6 days in placebo-treated controls. Adverse events were transient and well tolerated (Lancet. 2016 May 28;387[10034]:2226-34).

“A lot of medications have been tried for treatment of cocaine dependence, but actually none of them has been shown to be effective with the exception of substitution treatment with stimulants. Ours is one of the most successful trials. These patients were using cocaine an average of 24 days per month along with a lot of other drugs, despite being in heroin treatment for 4 years,” Dr. van den Brink said. “Patients were very willing to take the sustained-release dextroamphetamine. In the last 4 weeks, 84% of them used at least 80% of their medication. And they were blinded to what they were using.

“We saw good effect sizes: 0.6-0.7 for self-report measures and 0.31 for negative urine samples. So this is a very promising approach. But it also means that, like with tobacco dependence or alcohol dependence, we have to start thinking about substitution therapy in stimulant-dependent patients,” he said.

Dr. van den Brink said subanesthetic ketamine as a novel treatment for cocaine dependence is not yet ready for prime time use in clinical practice, because it’s just not practical to bring patients in for a roughly hour-long intravenous infusion on a daily basis, as was done in a highly impressive proof-of-concept study. But new formulations of ketamine are under development that should better lend themselves to use in clinical practice.

In the proof-of-concept study, investigators at the New York State Psychiatric Institute brought into the laboratory cocaine-dependent volunteers not seeking treatment or abstinence and administered 52-minute infusions of ketamine at 0.41 or 71 mg/kg or lorazepam at 2 mg (Biol Psychiatry. 2014 Jul 1;76[1]:40-6). Lorazepam had absolutely no effect on motivation to change, but ketamine was a different story.

“As soon as you give a low dose of ketamine, you see a wonderful effect on motivation to change and on craving ratings in assessments at 24 hours post infusion. This looks like another promising way of treating cocaine dependence,” he said.

Doxazosin for alcoholism

Investigators at the National Institute on Alcohol Abuse and Alcoholism and several U.S. universities hypothesized that the norepinephrine system could be an important treatment target in alcohol dependence. They conducted a double-blind, placebo-controlled randomized trial in which alcohol-dependent patients seeking outpatient treatment were assigned to the alpha1-adrenergic blocker doxazosin (Cardura) titrated to a maximum of 16 mg/day or placebo. They found doxazosin significantly reduced drinks per week and the number of heavy drinking days per week, but only in the subgroup of patients with a strong family history of alcoholism. In patients without such a family history, doxazosin paradoxically increased drinking (Addict Biol. 2016 Jul;21[4]:904-14).

One of the reasons adult ADHD is greatly underrecognized is that it tends to occur in combination with flashier substance use disorders. “Addiction is very comorbid with all kinds of disorders, but especially with externalizing childhood disorders like conduct disorder and ADHD,” Dr. van den Brink said.

It was shown half-a-decade ago that normal doses of methylphenidate have no effect on ADHD symptoms or substance use in comorbid adults. Then Swedish investigators reported that treating criminal offenders with high-dose methylphenidate – roughly three times greater than standard dosing – was effective in reducing both ADHD symptoms and comorbid substance use in criminal offenders. Those findings prompted investigators at the New York State Psychiatric Institute and the University of Minnesota to examine whether prescribing extended-release mixed amphetamine salts in adults with comorbid cocaine use disorder and ADHD would achieve improvement in both conditions. Indeed, it did, Dr. van den Brink said.

One hundred twenty-six affected patients were randomized to 60 or 80 mg/day of extended-release mixed amphetamine salts or placebo for 13 weeks coupled with weekly individual cognitive-behavioral therapy for all in this double-blind, three-arm clinical trial.

“They showed a number-needed-to-treat of about 2.5 in order to achieve a significant reduction in cocaine use and a very nice reduction in ADHD symptoms with a number-needed-to-treat of 3,” Dr. van den Brink said.

The rate of continuous cocaine abstinence in the last 3 weeks of the trial was 30% in the 80-mg group and 17.5% with 60 mg of extended-release mixed amphetamine salts, compared with just 7% with placebo (JAMA Psychiatry. 2015 Jun;72[6]:593-602).

Interpreting baclofen studies

The first high-quality multicenter, randomized, placebo-controlled, double-blind clinical trial, conducted in Germany, showed baclofen (Lioresal) at a mean dose of 180 mg/day was effective in maintaining alcohol abstinence (Eur Neuropsychopharmacol. 2015 Aug;25[8]:1167-77).

“They got wonderful results, with a number-needed-to-treat of 2.3. That is something we’re not used to seeing in the treatment of alcoholism. But there was no dose-response effect, which is a little unusual,” the psychiatrist observed.

Then a multicenter group of Dutch investigators, including Dr. van den Brink, carried out what they believed would be a confirmatory randomized, double-blind, placebo-controlled trial. However, it showed no difference between high- or low-dose baclofen and placebo in time to relapse (Eur Neuropsychopharmacol. 2016 Dec;26[12]:1950-9).

Little further light was shed by the two large French randomized, placebo-controlled clinical trials presented at the 2016 World Congress for Alcohol and Alcoholism in Berlin. One, the BACLOVILLE trial, included 320 patients treated in 60 family practice clinics; it showed strongly positive results for high-dose baclofen. In contrast, the 316-patient ALPADIR study proved negative. These conflicting results were particularly disappointing because France has been at the forefront of using high-dose baclofen to treat alcoholism, Dr. van den Brink said.

“Maybe some 100,000 people have been treated with high-dose baclofen for alcoholism in France,” he said. “What is the conclusion from all these baclofen studies? You can interpret them in many ways. Maybe there are two positive trials and two negative trials, or maybe there are two positive trials and two failed trials. The debate is not closed, even after four randomized trials.”

https://www.mdedge.com/clinicalpsychiatrynews/article/121238/addiction-medicine/ketamine-emerging-top-treatment-cocaine

Ketamine trials –

Researchers in the UK and US are running studies to see if ketamine could help prevent alcoholics from relapsing.

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People looking to quit problematic drinking in the UK could one day have access to a new, quick-acting treatment to help them cope with the difficult first few weeks of sobriety: ketamine.

In a new trial taking place at the University of Exeter and University College Hospital in London, researchers are using small shots of the tranquilizer—perhaps best known in the country as a popular party drug that can ruin the bladder lining of heavy users—alongside standard psychotherapy treatments to see if it can help treat alcoholism.

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“Current effects of treatments for alcoholism are at best modest, about three quarters of people return to drinking after 6 months, so there is a dire need for new treatments,” said Celia Morgan, a professor of psychopharmacology at the University of Exeter, and one of the lead researchers on the study.

“It could help people who are stuck in a rut with alcoholism. It may prime your brain to take on new experiences from the world.”

Ketamine has already been shown to be an effective treatment for depression, something that’s done a lot to rehabilitate its reputation. As an antidepressant it’s unique in that it acts very quickly, with patients often reporting an improvement in their mood over just one or two days.

That could make it ideal for treating recovering alcoholics, who often suffer from depression immediately after quitting.

“We know that in alcohol dependence, depression is a predictor of relapse in the first couple of weeks. So we’re able to give people the ketamine package in the time at which they might be particularly susceptible to relapse,” said Morgan.

The trial, which is funded by the UK government’s medical research charity, will have participants take part in seven therapy sessions, three with shots of ketamine. Control groups will receive no drug and no therapy conditions. Ideally, the ketamine will act as a sort of stabiliser for depression, and possibly increase the power of the therapy.

Morgan said experiments with animals show that ketamine may help form neuronal connections in the brain, and that could mean that in humans the therapy will be more effective or more likely to “stick.”

“There’s new scientific evidence in animal models suggesting that their brains might be primed to learn more [after taking ketamine,]” she said. “So it could help people who are stuck in a rut with alcoholism. It may prime your brain to take on new experiences from the world.”

“We’re not going for the full-blown mystical experience”

Morgan is not the only one pursuing this theory. Elias Dakwar, a Professor of Clinical Psychiatry at Columbia University in New York, is currently recruiting patients for a similar trial that will use ketamine treatment alongside motivational therapy for alcoholism. He says that the way people’s brains adapt to addiction is similar to that of depression.

“People sort of forswear their own agency and self-efficacy, and there’s a sense of resignation,” he said. “The thinking on ketamine’s effect on depression is that it reverses depression-related adaptation through neuroplasticity.”

In other words, it could make the brain more ready to create new connections and move away from old patterns of behaviour, making it an ideal companion for therapy that’s meant to help people re-evaluate and change their lives.

The ketamine doses Morgan plans to use are higher than those used in standard depression treatment, but they’re not quite enough to cause the sort of total dissociation that has led some scientists to class ketamine as a psychedelic drug, and far less than the maximum safe dose as an anaesthetic.

“We’re not going for the full-blown mystical experience,” Morgan said. “We’re looking at treatment we can do within the National Health Service as well; this is something that is funded by the government, so we are looking at things that are acceptable in that context.”

Both trials are still in the early stages: Morgan’s started in June and is set to run until 2017, and Dakwar’s should wrap up next year. But if the results are positive, ketamine’s use could expand quickly. Alcoholism, like most addictions, is notoriously difficult to treat, with few effective drugs available. And according to the NHS, nine percent of men and four percent of women in the UK show signs of alcohol dependence.

“It’s one of those really intractable disorders that people have been trying to find a drug therapy for some time,” said Dr Dakwar.