Tag: ketamine

Categories : Substance Use UrogenitalTags :

Ketamine is Giving More Young People Bladder Problems – An Expert Explains

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A growing number of people in the UK are using ketamine recreationally. Photo by Colin Davis on Unsplash

Heba Ghazal, Kingston University

Urology departments in England and Wales have reported seeing an increase in the number of 16- to 24-year-olds being admitted for bladder inflammation associated with ketamine use.

This appears to coincide with an increase in ketamine use – with the number of adults and teens entering treatment for ketamine abuse last year jumping substantially compared to even just a few years previously.

Ketamine abuse can have many affects on the bladder, causing frequent urination, night-time urination, sudden urges, leakage, inflammation, pain in the bladder or lower back and blood in the urine. These symptoms can be severe, make daily life very difficult and may even be permanent in some cases.

Ketamine was first approved in 1970 for human use as an anaesthetic. More recently, studies have suggested that ketamine used at low doses may have antidepressant effects.

But a growing number of people are now using ketamine recreationally. It acts as a dissociative drug, causing users to feel detached from themselves and their surroundings. It can produce hallucinogenic, stimulant and pain-relieving effects, which last one to two hours.

Users typically snort or smoke powdered ketamine, or inject liquid ketamine or mix it into drinks in order to experience the drug’s effects. Snorting usually produces stronger effects and more noticeable symptoms than swallowing it.

Ketamine users can develop tolerance to the drug quickly, needing higher doses to get the same effects. This is probably due to the body and brain adapting to become more efficient at breaking down the drug. Frequent users often need to take twice the amount of occasional users to get the same effect.

Bladder damage

Frequent, high-dose ketamine use can cause serious damage to the bladder, urinary tract and kidneys. In severe cases, the bladder may need to be removed.

The first recorded cases of ketamine affecting the bladder were reported in Canada in 2007, where nine people who used ketamine recreationally had severe bladder problems and blood in their urine. Later, a bigger study in Hong Kong found the same issues in 59 people who had used ketamine for more than three months.

Ketamine, as with any other drug, is metabolised in the body where it’s broken down and excreted in urine.

When ketamine is broken down, it turns into chemicals that can seriously harm the bladder. When these by-products stay in contact with the urinary tract for a long time, they irritate and damage the tissue.

The bladder is damaged first, because it holds urine the longest. Later, the ureters (tubes connecting the kidney to the bladder) and the kidneys can also be affected.

Over time, the bladder can shrink and become stiff, causing strong urinary symptoms. The ureters can become narrow and bent, sometimes described as looking like a “walking stick.” This can lead to backed-up urine in the kidneys (hydronephrosis).

Ketamine also increases oxidative stress, which damages cells and causes bladder cells to die. This breaks the protective bladder lining, making it leaky and overly sensitive.

All these changes can make the bladder overactive, extremely sensitive and painful, often causing severe urges to urinate and incontinence.

Bladder damage from ketamine use happens in stages.

In the first stage, the bladder becomes inflamed. This can often be reversed by stopping ketamine and taking certain medication – such as anti-inflammatory drugs, pain relievers or prescription drugs that reduce bladder urgency and help the bladder lining heal.

In the second stage, the bladder can shrink or become stiff. In this stage, treatment is similar to stage one, but a bladder wash may also be required. This is where a catheter is used to put liquid medication directly into the bladder. The drug coats the bladder’s inner lining, helping to restore its protective layer and reduce inflammation.

Botulinum toxin injections may also be used to relax the bladder and reduce pain and urgency. Stopping ketamine remains essential to prevent further damage.

In the final stage, permanent damage occurs to the bladder and kidneys. Over time, if the kidneys are affected, it can lead to kidney failure. Dialysis (a treatment where waste products and excess fluid are filtered from the blood) or even surgery may be required to repair kidney function and the urinary system.

Although ketamine has been a class B drug since 2014, it’s unfortunately affordable and accessible – costing as little as £3 per gram in some parts of the UK. Raising awareness about the risks of ketamine use is essential to prevent these serious health problems.

Heba Ghazal, Senior Lecturer, Pharmacy, Kingston University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Categories : AddictionTags :

Ketamine High not Why Treatment Works for Acohol Use Disorder, Study Finds

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Photo by Bruce Christianson on Unsplash

The psychedelic effects recreational users often seek from taking ketamine do not predict the therapeutic benefits for people being treated for alcohol use disorder, according to new research from King’s College London and University of Exeter.

The popular theory, which says that ketamine may have its therapeutic benefits because it produces strong psychedelic effects, has been called into question by the new study, published in Addiction. The findings suggest the treatment response may be down to other effects of the drug. 

The research, led by the Institute of Psychiatry, Psychology & Neuroscience at King’s, is the largest randomised controlled trial to date examining the use of intravenous ketamine-assisted psychotherapy for individuals with moderate to severe alcohol use disorder. It uses data from the Ketamine for reduction of Alcoholic Relapse (KARE) clinical trial at the University of Exeter and University College London.

For the first time, we thoroughly investigated the acute psychoactive effects of repeated ketamine infusions in people with alcohol use disorder. The effects didn’t predict ketamine’s therapeutic benefit, which leaves open other psychological or neural mechanisms that need to be investigated.

Dr Will Lawn, Senior Lecturer at King’s College London and study lead

Researchers carried out a secondary analysis of the KARE clinical trial which was conducted at two clinical research facilities in England involving 96 adult participants and sought to clarify the role of ketamine’s psychoactive effects in supporting abstinence from alcohol. 

Participants receiving three weekly infusions of intravenous ketamine reported marked psychoactive experiences, including altered reality, out-of-body sensations, and perceptual distortions, compared to those receiving placebo. These effects were consistently strong across all three dosing sessions. This suggests little to no development of tolerance to ketamine’s subjective effects over the short dosing schedule.

But despite the pronounced psychoactive effects, the study found no significant evidence that these experiences mediated ketamine’s therapeutic benefit in reducing alcohol consumption. The percentage of days abstinent from alcohol over six months was not predicted by the intensity of subjective drug effects.

A larger trial will explore ketamine’s effects in brain connection and function changes, as well as dosing.

Source: King’s College London

Categories : Mental HealthTags :

Ketamine no Benefit for Patients Hospitalised with Depression

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Researchers from Trinity College, St Patrick’s Mental Health Services, Queen’s University Belfast, Ireland, investigate use of twice-weekly ketamine infusions as an add-on treatment for inpatients with serious depression

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Findings from a randomised and blinded clinical trial investigating repeated ketamine infusions for treating depression have revealed no extra benefit for ketamine when added onto standard care for people admitted to hospital for depression. The paper is published in the journal JAMA Psychiatry.

The KARMA-Dep (2) Trial involved researchers from St Patrick’s Mental Health Services, Trinity College Dublin, and Queens University Belfast, Ireland. It was sponsored by Trinity College Dublin  and led by Declan McLoughlin, Research Professor of Psychiatry at Trinity College Dublin and Consultant Psychiatrist at St Patrick’s Mental Health Services.

Depression has been recognised by the World Health Organization as a leading cause of disability globally.  According to the Health Research Board’s most recent report, there were 15 631 adult admissions to psychiatric services in Ireland in 2023. Similar to previous years, depressive disorders accounted for the highest proportion (about 24%) of all admissions.

Studies show that about 30% of people with depression do not respond sufficiently well to conventional antidepressants, which mostly target monoamine neurotransmitters, for example serotonin, dopamine and noradrenaline.  There is thus a need for new treatments.  One such novel treatment is the dissociative anaesthetic ketamine when given intravenously in low sub-anaesthetic doses. Ketamine works differently to other antidepressants and is believed to mediate its effects in the brain through the chemical messenger glutamate.

Single infusions of ketamine have been reported to produce rapid antidepressant effects, but these disappear within days. Nonetheless, ketamine is increasingly being adopted as an off-label treatment for depression even though the evidence to support this practice is limited. One possibility is that repeated ketamine infusions may have more sustained benefit. However, this has so far been evaluated in only a small number of trials that have used an adequate control condition to mask the obvious dissociative effects of ketamine, e.g. altered consciousness and perceptions of oneself and one’s environment. 

KARMA-Dep 2 is an investigator-led trial, sponsored by Trinity College Dublin and  funded by the Health Research Board. The randomised trial was developed to assess antidepressant efficacy, safety, cost-effectiveness, and quality of life during and after serial ketamine infusions when compared to a psychoactive comparison drug midazolam. Trial participants were randomised to receive up to eight infusions of either ketamine or midazolam, given over four weeks, in addition to all other aspects of usual inpatient care. 

 The trial findings revealed that:

  • There was no significant difference between the ketamine and midazolam groups at the end of the treatment course on the trial’s primary outcome, which was an objective measurement of depression. This was assessed with the commonly used Montgomery-Åsberg Depression Rating Scale (MADRS).
  • There was no significant difference between the two groups at the end of the treatment course on a subjective, patient-rated, scale for depression.  This was assessed with the commonly used Quick Inventory of Depressive Symptoms, Self-Report scale (QIDS-SR-16). 
  • No significant differences were found between the ketamine and midazolam groups on secondary outcomes for cognitive, economic or quality-of-life outcomes. 
  • Despite best efforts to keep the trial patients and researchers blinded about the randomised treatment, the vast majority of patients and raters correctly guessed the treatment allocation. This could lead to enhanced placebo effects.

Speaking about the impact of the findings, Declan McLoughlin, Research Professor of Psychiatry at Trinity College Dublin and Consultant Psychiatrist at St Patrick’s Mental Health Services, said:

“Our initial hypothesis was that repeated ketamine infusions for people hospitalised with depression would improve mood outcomes. However, we found this not to be the case. Under rigorous clinical trial conditions, adjunctive ketamine provided no additional benefit to routine inpatient care during the initial treatment phase or the six-month follow-up period. Previous estimates of ketamine’s antidepressant efficacy may have been overstated, highlighting the need for recalibrated expectations in clinical practice.” 

Lead author of the study, Dr Ana Jelovac, Trinity College Dublin, said:

“Our trial highlights the importance of reporting the success, or lack thereof, of blinding in clinical trials. Especially in clinical trials of therapies where maintaining the blind is difficult, e.g. ketamine, psychedelics, brain stimulation therapies. Such problems can lead to enhanced placebo effects and skewed trial results that can over-inflate real treatment effects.”.

Source: Trinity College Dublin

Categories : Pain ManagementTags :

Off-label Use of Ketamine for Chronic Pain is Unsupported by Evidence

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Results show no clear evidence of benefit for ketamine in chronic pain and identified an increased risk of adverse effects such as delusions, delirium, paranoia, nausea, and vomiting

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The off-label use of ketamine to treat chronic pain is not supported by scientific evidence, a new Cochrane review has found.

Ketamine is an anaesthetic commonly used for procedural sedation and short-term pain relief. Ketamine is also frequently prescribed off-label to manage chronic pain conditions such as nerve pain, fibromyalgia and complex regional pain syndrome. It is one of several NMDA receptor antagonists – a group of drugs thought to reduce pain by blocking certain brain receptors involved in pain signalling.

The review, conducted by researchers from UNSW Sydney, Neuroscience Research Australia (NeuRA), and Brunel University of London, examined 67 trials involving over 2300 adult participants. It assessed five NMDA receptor antagonists: ketamine, memantine, dextromethorphan, amantadine, and magnesium.

Results show no clear evidence of benefit for ketamine in chronic pain and identified an increased risk of adverse effects such as delusions, delirium, paranoia, nausea, and vomiting. Evidence was rated low to very low certainty, due to small study sizes and poor methodological quality.

“We want to be clear – we’re not saying ketamine is ineffective, but there’s a lot of uncertainty,” said Michael Ferraro, Doctoral Candidate at UNSW and NeuRA, first author of the review. “The data could point to a benefit or no effect at all. Right now, we just don’t know.”

Researchers looked at the effects across various chronic pain conditions and dosing strategies but found no clear evidence of benefit in any specific condition or dose. Side effects were a major concern, particularly with intravenous use.

“The most common adverse events we saw were psychotomimetic effects such as delusions, delirium and paranoia, as well as nausea and vomiting.” said Ferraro. “These effects are distressing for many patients. Clinicians often try to balance the dose for pain relief without triggering those symptoms, but this isn’t always achieved.”

The review also found no studies that reported on two key outcomes: whether ketamine reduced depressive symptoms or opioid use. This is notable, as ketamine is often proposed for patients with depressive symptoms or opioid tolerance.

“This group of drugs, and ketamine in particular, are in relatively common use for chronic pain around the world. Yet we have no convincing evidence that they are delivering meaningful benefits for people with pain, even in the short term,” said Neil O’Connell, Professor at Brunel University of London, co-senior author of the review. “That seems a good reason to be cautious in the clinic and clearly indicates an urgent need to undertake high quality trials.”

The authors hope the review will help inform patients and clinicians weighing up potential benefits and harms, and guide future research. While more evidence is needed, this review highlights the importance of high-quality trials to understand whether ketamine has a role in chronic pain care.

“We’ve seen the harm that can come from taking medicines developed for acute pain and applying them to chronic pain, opioids are a prime example. Now we’re seeing a similar pattern with ketamine,” said co-senior author James McAuley, Professor at UNSW and senior researcher at NeuRA . “As opioid prescribing is slowly reduced, there’s a growing demand for alternatives, but we need to be careful not to rush into widespread use without strong evidence.”

Source: Cochrane

Categories : Mental Health NeurologyTags :

Extending Ketamine’s Relieving Effect on Depression

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For 30% of people with major depressive disorder (MDD), antidepressants don’t work. When infused at a low dose, ketamine shows remarkable efficacy as a rapidly acting antidepressant, with effects observed within hours even in patients who have been resistant to other antidepressant treatments. One drawback is that consistent infusions of ketamine are needed to maintain symptoms at bay, which could result in side effects, such as dissociative behaviours and the possibility of addiction, and stopping treatment can result in relapse.

In a new study published in Science, Lisa Monteggia’s and Ege Kavalali’s labs show that it is feasible to substantially extend the efficacy of a single dose of ketamine from its current duration of up to a week to a longer period of up to two months.

“The premise of this study, which was led by Zhenzhong Ma, a fantastic research assistant professor, was based on a testable mechanistic model that we developed that accounts for ketamine’s rapid antidepressant action,” Monteggia said.

Previously, researchers in the field had determined that ketamine’s antidepressant effect requires the activation of a key signalling pathway called ERK, but only ketamine’s long-term effects – not its rapid effects – are abolished when ERK is inhibited. As a fast-acting antidepressant, ketamine relies on ERK-dependent synaptic plasticity to produce its rapid behavioural effects. Ma and colleagues hypothesised that they could maintain ketamine’s effects for longer periods by enhancing ERK activity. 

In the recent paper, Ma discovered that ketamine’s antidepressant effects could be sustained for up to two months by using a drug called BCI, which inhibits a protein phosphatase and results in increased ERK activity. By inhibiting the phosphatase, the authors retained ERK’s activity and augmented the synaptic plasticity that drives ketamine’s prolonged antidepressant effects. 

lthough the use of BCI makes the application of these results to the clinic difficult, Monteggia said that the results provide a proof of principle that ketamine’s antidepressant action can be sustained by targeting intracellular signaling. She and Kavalali, the William Stokes Professor of Experimental Therapeutics and the chair of the Department of Pharmacology, have worked on the project since its inception and hope that it will foster other studies looking to identify specific molecules to enhance and sustain the action of a single dose of ketamine.

Ultimately, this work will be a stepping stone toward improving MDD patients’ lives by reducing the burden of treatment.

Source: Vanderbilt University

Categories : Mental HealthTags :

A Ketamine Depression Treatment in a Safer Oral Tablet Form

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A University of Otago-led clinical trial has tested an oral form of ketamine therapy for treatment-resistant depression that has fewer side effects whilst also reducing the risk of abusing the powerful, tightly-regulated anaesthetic.

Working in collaboration with New Zealand’s Douglas Pharmaceuticals, researchers have conducted a trial of ketamine in an extended-release tablet form. The study, published in Nature Medicine, involved 168 adults for whom regular anti-depressant therapy repeatedly failed. They either took a range of oral doses of ketamine or a placebo for 12 weeks.

Professor Paul Glue, Otago’s Hazel Buckland Chair in Psychological Medicine, says the highest dose of ketamine – 180mg – showed significant improvement in depressive symptoms, compared with patients who received placebo.

“Ketamine can be given by injection or nasal spray, but these methods can leave people feeling spaced out, sedated, and increases their blood pressure. This study shows the extended-release ketamine tablets are safe and effective, and overall, tolerability was good, with participants reporting minimal side effects,” he says.

Douglas Pharmaceuticals is now seeking the interest of partners to complete registrational clinical trials and prepare for commercialisation of the tablets.

“We have found there are many people, here in New Zealand and around the world, who have treatment-resistant depression, and who have no or very little chance of accessing ketamine. Because most doses of this tablet formulation can be taken at home, this is potentially a much cheaper and convenient option for these patients compared with weekly clinic visits for ketamine injections or nasal sprays.”

Ketamine has been used legally by doctors in New Zealand since the 1970s for sedation and pain relief, but it has been classified as an illegal drug for recreational use since the 1980s.

Professor Glue says having the drug in a tablet form reduces the risk of abuse as the manufacturing process makes them difficult to manipulate.

Source: University of Otago

Categories : Mental HealthTags :

Questions Remain over Ketamine’s Promise for Treating Depression

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Using the old anaesthesia drug ketamine to pull people out of the depths of severe depression has gone from fringe idea to widespread use in just a few years. Sparked by promising studies and stories of lives transformed, clinics offering intravenous infusions of ketamine have popped up in the US. Some also offer a newer, more expensive, nasal spray version.

But major questions remain about who ketamine can help, why some people get tremendous relief within days or weeks while others don’t, and the costs and benefits of different ways of delivering the drug.

New findings just came out from a study that seeks to answer some of those questions. They add more evidence about the power of IV ketamine to help some of the most severely ill people with depression or bipolar disorder who haven’t gotten relief from other treatments, including many who have frequent suicidal thoughts.

Called Bio-K, the study involved 74 people treated at four clinics in Michigan, Maryland and Minnesota. After just three infusions of ketamine over 11 days, 52% of participants saw their severe depression ease so much they achieved remission. Another 15% responded somewhat.

Half of those who had thought often of suicide before receiving ketamine experienced a dramatic drop in those impulses. The results are published in the Journal of Affective Disorders.

“These participants are very representative of the sickest patients we see, with more than 80% reporting suicidality that would have excluded them from other depression treatment studies,” said University of Michigan Health psychiatrist and study leader Sagar Parikh, MD.

“As in other studies of ketamine, the initial response to treatment was a strong predictor of who would do well,” he added. “Two-thirds of those who responded after one infusion went on to achieve remission, while those who hadn’t responded measurably after two infusions were unlikely to start to respond after an additional one.”

Who responds and why?

What’s the difference between them and those who responded? That’s a key focus of Bio-K, which is funded by donors to the U-M Eisenberg Family Depression Center.

A third of all Bio-K participants didn’t respond to ketamine by the end of the three infusions provided under the study, leaving them to cope with one more failure in a series of attempted treatments.

The team’s in-depth interviews with some of these non-responders show how difficult that can be, as the team reported in a paper last year.

By studying molecules in blood samples from the study’s participants, the Bio-K team hopes to find biomarkers that could predict who is most likely to get relief from ketamine, and who should try other options.

The study is evaluating cell signaling proteins, inflammatory markers and molecules that can indicate rates of cell metabolism in mitochondria. Early results from those analyses should be available in the next year.

From research to clinical use

In the meantime, the strength of the response in Bio-K participants helped fuel the founding of an IV ketamine clinic at University of Michigan Health, says Parikh, who oversees the clinic.

U-M now accepts referrals from providers across the region who have patients with treatment-resistant depression and need another option after trying at least four medications.

Patients come to the main U-M medical campus around eight times during the span of a month for infusions under the care of psychiatrists, anaesthesiologists and other clinicians.

Parikh and his colleagues even wrote a guide for other hospitals on how best to set up and run such a clinic.

A newer version

Meanwhile, the nasal spray form of ketamine, called esketamine and sold under the name Spravato, has captured attention in recent years for its potential to ease disabling and life threatening symptoms without requiring an IV.

The spray involves a form of the drug manufactured by a pharmaceutical company in a way that isolates just one variety of the ketamine molecule, which allowed the company to seek a specific FDA approval.

Parikh notes that U-M was one of the sites for the original small study that led to Spravato’s approval by the FDA, and another larger study sponsored by Janssen, the drug’s manufacturer, that recently concluded. In addition to serving as the local principal investigator for these studies, Parikh also briefly served as a consultant to the company.

Based on the experience in these studies, U-M hopes to start offering Spravato alongside IV ketamine on a clinical basis. Even though it’s not given through an intravenous drip, the nasal spray still requires careful observation of patients under the FDA’s approval conditions.

IV vs nasal spray

Even as researchers search for biomarkers to predict ketamine response, clinicians find themselves with a conundrum: Which patients should start with IV ketamine, and which with Spravato? And how do the two compare head to head in actual response to treatment?

That’s what researchers at Yale University, U-M and their colleagues will soon try to find out, through a new study just funded by the federal Patient-Centered Outcomes Research Institute.

The study, which will begin enrolling up to 400 people at six sites nationwide later this year, will randomly assign people with treatment resistant depression to either the IV or nasal spray form of the drug. They’ll then receive that treatment for about four weeks, and have their symptoms monitored during treatment and for months afterward.

Such a head-to-head study might help inform insurers that haven’t yet started covering one or both forms of ketamine, Parikh noted.

More about the Bio-K results

In the meantime, the treatment response results from the Bio-K study and other studies can help more patients and clinicians understand the impact of IV ketamine.

Although Bio-K accepted people who were suicidal, which many antidepressant medication studies do not, it did not include people who use cannabis or those who have an active substance use disorder, schizophrenia or psychosis. But participants had to have failed to respond to at least two antidepressant or mood stabilising medications after at least eight weeks, or failed to respond to six sessions of ECT, the treatment based on electric stimulation of the brain that has been seen as the last resort for many patients.

The study found that it did not matter if they got their infusions slowly over 100 minutes or in a standard session of 40 minutes.

At the start of the study, the average score of participants on a standard depression scale called MADRS was 28; that average dropped to 11 at 24 hours after the third infusion. A score of 10 or below is considered depression free, or remission, and a drop in score of at least 50% of the total score is considered response. In all, 67% achieved what is considered response, and 52% reached remission.

Source: Michigan Medicine – University of Michigan

Categories : Mental Health NeurologyTags :

Scientists may have Found out How Rapid-acting Antidepressants Work

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Rapid-acting antidepressants, including ketamine, scopolamine and psilocybin, have been found to have immediate and lasting positive effects on mood in patients with major depressive disorder but how these effects arise is unknown. New research led by the University of Bristol and published in Science Translational Medicine explored their neuropsychological effects and found that all three of these drugs can modulate affective biases associated with learning and memory.

Negative affective biases are a core feature of major depressive disorder. Affective biases occur when emotions alter how the brain processes information and negative affective biases are thought to contribute to the development and continuation of depressed mood.

The research team used an affective bias test, based on an associative learning task, to investigate the effects of rapid-acting antidepressants (RAADs) in rats.

They found that all the treatments were able to reduce negative affective biases associated with past experiences but there were additional characteristics of the dissociative anaesthetic, ketamine, and the serotonergic psychedelic, investigational COMP360 psilocybin (Compass Pathways’ proprietary formulation of synthetic psilocybin), which could explain why the effects of a single treatment can be long-lasting.

The findings suggest that these sustained effects are due to adaptive changes in the brain circuits which control affective biases, and these can influence how past experiences are remembered.

The effects at low doses were very specific to affective bias modulation and were localised to the prefrontal cortex of the brain, a region known to play an important role in mood.

Emma Robinson, Professor of Psychopharmacology in the School of Physiology, Pharmacology & Neuroscience at Bristol, and lead author, said: “Using a behavioural task we showed that drugs that are believed to have rapid and sustained benefits in depressed patients, specifically modulate affective biases associated with past experiences, something which we think is really important for understanding why they can improve a patient’s mood so quickly.

“We also found differences in how ketamine, scopolamine and COMP360 psilocybin interact with these neuropsychological mechanisms which may explain why the effects of a single treatment in human patients can be long-lasting, days (ketamine) to months (psilocybin).

“By using an animal model, we have been able to investigate these important interactions with learning and memory processes and neural plasticity and propose a two-stage model that may explain the effects we observe.”

In the task, each animal learnt to associate a specific digging material with a food reward under either treatment or control conditions.

The treatment condition is designed to generate a change in the animal’s affective state and a choice test is used to quantify the affective bias this generates.

Acute treatment with the RAADs ketamine, scopolamine, or psilocybin prevented the retrieval of the negative affective bias induced in this model.

However, the most exciting finding was at 24 hours after treatment when low, but not high, doses of ketamine and psilocybin led to a re-learning effect where the negatively biased memory was retrieved with a more positive affective valence.

Only psilocybin, but not ketamine or scopolamine treatment also positively biased new experiences.

Exploring in more detail the re-learning effects of ketamine in the studies, the researchers found they were protein synthesis-dependent, localised to the medial prefrontal cortex and could be modulated by cue-reactivation, consistent with their predictions of experience-dependent neural plasticity.

The study’s findings propose a neuropsychological mechanism that may explain both the immediate and sustained effects of RAADs, potentially linking their effects on neural plasticity with mood.

Source: University of Bristol

Categories : Mental HealthTags :

Ketamine’s Effect on Depression is Essentially Placebo Effect

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Over the years, studies have demonstrated the psychoactive drug ketamine’s effect on depression, providing profound and fast relief to many people. But these studies have a critical flaw: participants usually can tell whether they have been given ketamine or a placebo. Even in blinded trials in which participants are not told which they received, ketamine’s oftentimes trippy effects are a dead giveaway.

In a new study published in Nature Mental Health, Stanford Medicine researchers devised a clever workaround to hide the psychedelic, or dissociative, properties of the anesthetic first developed in 1962. They recruited 40 participants with moderate to severe depression who were also scheduled for routine surgery, then administered a single infusion of ketamine (0.5 mg kg−1) or placebo (saline) during usual anaesthesia.

All researchers and clinicians involved in the trial also were blinded to which treatment patients received. The treatments were revealed two weeks later.

The researchers were amazed to find that both groups experienced the large improvement in depression symptoms usually seen with ketamine.

“I was very surprised to see this result, especially having talked to some of those patients who said ‘My life is changed, I’ve never felt this way before,’ but they were in the placebo group,” said Boris Heifets, MD, PhD, assistant professor of anaesthesiology, perioperative and pain medicine, and senior author.

Just one day after treatment, both the ketamine and placebo groups’ scores on the Montgomery-Åsberg depression rating scale (MADRS) dropped, on average, by half. Their scores stayed roughly the same throughout the two-week follow-up.

“To put that into perspective, that brings them down to a category of mild depression from what had been debilitating levels of depression,” said Theresa Lii, MD, a postdoctoral scholar in the Heifets lab and lead author of the study.

What does it all mean?

The researchers concede that their study, having taken an unexpected turn, raises more questions than it answers.

“Now all the interpretations happen,” said Alan Schatzberg, MD, a co-author of the study. “It’s like looking at a Picasso painting.”

The researchers determined that it was unlikely the surgeries and general anaesthesia account for the improvements because studies have found that depression generally does not change after surgery; sometimes, it worsens.

A more likely interpretation, the researchers said, is that participants’ positive expectations may play a key role in ketamine’s effectiveness.

At their last follow-up visit, participants were asked to guess which intervention they had received. About a quarter said they didn’t know. Of those who ventured a guess, more than 60% guessed ketamine.

Their guesses did not correlate with their treatment – confirmation of effective blinding – but rather with how much better they felt.

Source: Stanford Medicine

Categories : Mental HealthTags :

Generic Ketamine Performs Strongly for Treatment-resistant Depression

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A low-cost version of ketamine to treat severe depression has performed strongly in a placebo-controlled double-blind trial. Results published in the British Journal of Psychiatry showed that more than one in five participants achieved total remission from their symptoms after a month of bi-weekly injections, while a third had their symptoms improve by at least 50%.

“For people with treatment-resistant depression – so those who have not benefitted from different modes of talk-therapy, commonly prescribed antidepressants, or electroconvulsive therapy – 20 per cent remission is actually quite good,” lead researcher Professor Colleen Loo says.

“We found that in this trial, ketamine was clearly better than the placebo – with 20 per cent reporting they no longer had clinical depression compared with only 2 per cent in the placebo group. This is a huge and very obvious difference and brings definitive evidence to the field which only had past smaller trials that compared ketamine with placebo.”

How the trial worked

The researchers, led by UNSW Sydney and the affiliated Black Dog Institute, recruited 179 people with treatment-resistant depression. All were given an injection of either a generic form of ketamine that is already widely available in Australia as a drug for anaesthesia and sedation – or placebo. Participants received two injections a week in a clinic where they were monitored for around two hours while acute dissociative and sedative effects wore off, usually within the first hour. The treatment ran for a month and participants were asked to assess their mood at the end of the trial and one month later.

In this double-blind trial, a placebo was chosen that also causes sedation, to improve treatment masking. Midazolam is a sedative normally administered before a general anaesthetic, while in many previous studies the placebo was saline.

“Because there are no subjective effects from the saline, in previous studies it became obvious which people were receiving the ketamine and which people received placebo,” Prof Loo says.

“In using midazolam – which is not a treatment for depression, but does make you feel a bit woozy and out of it – you have much less chance of knowing whether you have received ketamine, which has similar acute effects.”

Other features of the recent trial that set it apart from past studies included accepting people into the trial who had previously received electroconvulsive therapy (ECT).

“People are recommended ECT treatment for their depression when all other treatments have been ineffective,” Prof. Loo says.

“Most studies exclude people who have had ECT because it is very hard for a new treatment to work where ECT has not.”

Another difference about this trial was that the drug was delivered subcutaneously (injected into the skin) rather than by drip, thus greatly reducing time and medical complexity. The study is also the largest in the world to date that compares generic ketamine with placebo in treating severe depression.

Much more affordable

Apart from the positive results, one of the standout benefits of using generic ketamine for treatment-resistant depression is that it is much cheaper than the patented S-ketamine nasal spray currently in use in Australia. Where S-ketamine costs about AUS$800 (R9 600) per dose, the generic ketamine is a mere fraction of that, costing as little as AUS$5 (R60), depending on the supplier and whether the hospital buys it wholesale. On top of the cost for the drug, patients need to pay for the medical care they receive to ensure their experience is safe – which at Black Dog Institute clinics, comes to AUS$350 (R4200) per session.

“With the S-ketamine nasal spray, you are out of pocket by about AUS$1200 for every treatment by the time you pay for the drug and the procedure, whereas for generic ketamine, you’re paying around AUS$300-350 for the treatment including the drug cost,” Prof Loo says.

She adds that for both S-ketamine and generic ketamine treatments, the positive effects often wear off after a few days to weeks, so ongoing treatment may be required, depending on someone’s clinical situation. But the prohibitive costs of the drug and procedure make this an unsustainable proposition for most.

The researchers will next be looking at larger trials of generic ketamine over longer periods, and refining the safety monitoring of treatment.

Source: University of New South Wales