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The role of belief in ketamine as a treatment for depression

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The role of belief in ketamine as a treatment for depression

Multiple studies have shown that ketamine is a fast acting treatment for depression, but a key issue with the studies is that many participants can tell if they have been given ketamine or a placebo. 

A new study from Stanford Medicine has worked around this by administering participants scheduled for surgery with either ketamine or a placebo when the participants were in surgery and under general anesthesia.

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

See also  Esketamine outperforms standard major depression treatment, study shows

The researchers found that both groups experienced a large improvement in depression symptoms usually seen with ketamine.

The study has been published in Nature Mental Health.

“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 anesthesiology, perioperative and pain medicine, and senior author of the study.

One day after treatment, both groups’ scores on the Montgomery-Åsberg depression rating scale dropped, on average, by half and 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.

The researchers concede that their study raises more questions than it answers.

“Now all the interpretations happen,” said Alan Schatzberg, MD, the Kenneth T. Norris, Jr. Professor in Psychiatry and Behavioral Sciences and 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 anesthesia account for the improvements because studies have found that depression generally does not change after surgery; sometimes, it worsens.

A more likely interpretation is that participants’ positive expectations may play a key role in ketamine’s effectiveness. When participants were asked to guess which intervention they had received, a quarter said they didn’t know and more than 60% guessed ketamine.

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

“In some ways none of this is new,” Heifets said. “Placebo is probably the single most effective, consistent intervention in medicine, full stop. It’s seen in every trial, and we should probably be paying more attention to the factors that give rise to it.”

These factors might include how a study is described; interactions with health care professionals; and, in this case, the unavoidable media hype around ketamine.

“We’ll need to devise more clever experiments to tease apart the direct pharmacological effects from the psychological effects of taking ketamine and other psychedelics,” Schatzberg added.

“The take-away should not be that ketamine “is just a placebo,” Heifets said.

Schatzberg continued: “Saying ‘it’s just a placebo’ is really a disservice to what placebo is,” he said. “It isn’t ‘I’ll feel better if I say it enough times,’ and it does not imply that there was nothing wrong with the patient.”

The researchers suggest there may be physiological resonance between the placebo effect — hope — and how ketamine works. Studies suggest that both may be mediated in part by the brain’s μ-opioid receptors, which process pain.

“There is most definitely a physiological mechanism, something that happens between your ears, when you instill hope,” Heifets said.

The results also suggest that the psychedelic experience may not be crucial to ketamine’s benefits, though it likely encourages more positive expectations.

“Maybe with a non-hallucinogenic psychedelic analog you can get the same benefits without having to, you know, go to outer space,” Heifets said.

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Mapping the effects of ketamine on the brain

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Mapping the effects of ketamine on the brain

A new study has mapped the effects of ketamine on the brain, finding that repeated use over extended periods creates widespread structural changes in the brain’s dopamine system.

The study found that repeated ketamine exposure leads to a decrease in dopamine neurons in midbrain regions linked to regulating mood. They also revealed an increase in dopamine neurons in the hypothalamus, which regulates the body’s basic functions like metabolism and homeostasis.

A former finding that ketamine decreases dopamine in the midbrain, may indicate why long-term abuse of ketamine could cause users to exhibit similar symptoms to people with schizophrenia. 

The researchers suggest that their new finding that ketamine increases dopamine in the parts of the brain that regulate metabolism, published in Cell Reports, may help explain why it shows promise in treating eating disorders.

They suggest this strengthens the case for developing ketamine therapies that target specific areas of the brain, rather than administering doses that wash the entire brain in ketamine.

Raju Tomer, the senior author of the paper, stated: “Instead of bathing the entire brain in ketamine, as most therapies now do, our whole-brain mapping data indicates that a safer approach would be to target specific parts of the brain with it, so as to minimise unintended effects on other dopamine regions of the brain.”

Tracking detailed data

The researchers tracked highly detailed data that enabled them to track how ketamine affects dopamine networks across the brain. 

The insight revealed that ketamine reduced the density of dopamine axons (nerve fibers) in the areas of the brain responsible for hearing and vision, while increasing dopamine axons in the brain’s cognitive centers, which may help explain the dissociative behavioral effects observed in individuals exposed to ketamine.

Malika Datta, a co-author of the paper, added: “The restructuring of the brain’s dopamine system that we see after repeated ketamine use may be linked to cognitive behavioral changes over time.”

Most studies of ketamine’s effects on the brain to-date have looked at the effects of acute exposure – how one dose affects the brain in the immediate term. 

For this study, researchers examined repeated daily exposure over the course of up to ten days. Statistically significant alterations to the brain’s dopamine makeup were only measurably detectable after ten days of daily ketamine use. 

The researchers also assessed the effects of repeated exposure to the drug at two doses, one dose analogous to the dose used to model depression treatment in mice, and another closer to the dose that induces anesthesia. The drug’s effects on dopamine system were visible at both doses.

“The study is charting a new technological frontier in how to conduct high-resolution studies of the entire brain,” said Yannan Chen, paper co-author. 

It is the first successful attempt to map changes induced by chronic ketamine exposure at what is known as “sub-cellular resolution,” in other words, down to the level of seeing ketamine’s effects on parts of individual cells.

Most sub-cellular studies of ketamine’s effects conducted to date have been hypothesis-driven investigations of one area of the brain that researchers have targeted because they believed that it might play an important role in how the brain metabolises the drug. 

This study is the first sub-cellular study to examine the entire brain without first forming such a hypothesis.

Bradley Miller, a Columbia psychiatrist and neuroscientist who focuses on depression, said: “Ketamine rapidly resolves depression in many patients with treatment-resistant depression, and it is being investigated for longer-term use to prevent the relapse of depression. 

“This study reveals how ketamine rewires the brain with repeated use. This is an essential step for developing targeted treatments that effectively treat depression without some of the unwanted side effects of ketamine.”

“This study gives us a deeper brain-wide perspective of how ketamine functions that we hope will contribute to improved uses of this highly promising drug in various clinical settings as well as help minimise its recreational abuse. More broadly, the study demonstrates that the same type of neurons located in different brain regions can be affected differently by the same drug,” added Tomer.

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Psilocybin analogue shows positive results in Phase 2 depression study

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Psilocybin analogue shows positive results in Phase 2 depression study

Cybin has announced positive Phase 2 topline safety and efficacy data for its proprietary deuterated psilocybin analogue – CYB003 – for the treatment of major depressive disorder (MDD).

Results from Cybin’s study have shown that 79% of patients were in remission from depression at six weeks after receiving two doses of CYB003.

CYB003 demonstrated a large improvement in symptoms after one dose and a total of 79% of patients were responsive to the treatment. The compound also demonstrated an excellent safety profile in doses tested, with all reported adverse events mild to moderate and self–limiting.

Additionally, Cybin has stated that the magnitude of improvement was superior compared to approved antidepressants and recently reported data with other psychedelics, stating that the effects translate into an unprecedented effect size.

The company has said that the results compare favorably to pooled data from 232 industry studies of current standard-of-care antidepressants, SSRIs, submitted to the FDA.

The announcement follows Phase 2 interim results in early November 2023, which demonstrated that CYB003 saw a “rapid, robust and statistically significant reduction in symptoms of depression three weeks following a single 12mg dose compared to placebo”.

Cybin CEO, Doug Drysdale, stated: “We are delighted to share that CYB003 achieved the primary efficacy endpoint in this study and showed rapid and statistically significant improvements in depression symptoms after a single dose, with a clear incremental benefit of a second dose, resulting in four out of five patients in remission from their depression at six weeks.

“This is an impressive finding and follows on from the unprecedented interim results we announced earlier this month.”

Drysdale emphasised that the strength of the data will support CYB003 into Phase 3 of the study.

Cybin CMO, Amir Inamdar, added: “The significant reduction in depression symptoms observed in our Phase 2 study is highly gratifying.

“At the three-week primary efficacy endpoint, a single 12mg dose of CYB003 showed a rapid, robust, and highly statistically significant improvement in depression symptoms compared to placebo, with a -14.08 point difference in change from baseline in MADRS. 

“This translated into a very large effect size. Similar significant and robust effects were also seen with a single 16mg dose, which resulted in an improvement in symptoms of depression as measured using the MADRS total score by about 13 points versus placebo. 

“These effects were evident on day one with the 16mg dose and were also highly statistically significant. When data from 12mg and 16mg are pooled, these robust effects are maintained. Further, with two doses, response and remission rates in excess of 75% were observed with CYB003 (12mg). 

“With these findings in hand, we are encouraged by the potential of CYB003 to help those with MDD and look forward to progressing to a multinational, multisite Phase 3 study early next year.”

Cybin is planning on submitting topline data to the FDA with an aim to hold a Phase 2 meeting in Q1 of 2024, with further 12-week durability data from Phase 2 CYB003 expected in Q1, and recruitment for the Phase 3 study anticipated to begin by the end of Q1 2024.

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Clerkenwell Health calls for volunteers to support groundbreaking psychedelic research

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Clerkenwell Health calls for volunteers to support groundbreaking psychedelic research

Mental health research provider Clerkenwell Health is calling for volunteers to join its groundbreaking clinical trials that will research whether psychedelics can provide effective treatments for complex mental health conditions.

Clerkenwell is seeking a diverse group of volunteers from across the UK between 18 and 65 years old to take part in the trials if they suffer from a relevant condition. 

The trials, which will be conducted at Clerkenwell Health’s purpose-built facility near Harley Street in London, are being run in partnership with a number of world-leading drug developers to test whether psychedelic drugs – often combined with talking therapy – can offer a new approach to treating a variety of mental health illnesses.

See also  Clerkenwell Health is launching a free UK psychedelic therapist training programme

Clerkenwell Health is seeking volunteers for trials that look to find cures for a range of conditions, including PTSD, depression, alcohol use disorder and anorexia. 

Many of the conditions have few successful treatment options and Clerkenwell’s innovative methods of combining psychedelics with therapy aim to to treat these problems more holistically, providing long-term quality of life for patients.

Chief Scientific Officer at Clerkenwell Health, Dr Henry Fisher, said: “With the current system for treating mental health disorders simply not working, we’re calling for patients to help identify the next wave of treatments. 

“These have the potential to be groundbreaking for the millions of people across the UK who are affected by poor mental health.

“The status quo for mental health treatment has not only resulted in patients experiencing debilitating side-effects, huge waiting lists and high relapse rates, but is costly, complicated and broadly ineffective. 

“By participating in upcoming clinical trials, patients have an opportunity to make a valuable contribution to growing research which will support the development of the next generation treatments for mental health conditions.”

According to MIND, approximately 1 in 4 people in the UK will be affected by a mental health condition each year and with a significant rise in people contacting mental health services in recent years, there has never been a more desperate need to identify new and innovative treatments.

Given the challenges facing the country’s health service and with mental health challenges on the rise, the search for volunteers to test effective treatments has never been more pressing. 

Clerkenwell has stated, in this regard, that it has gone national with its search for volunteers in an effort to deliver medical breakthroughs in mental health akin to the Polio clinical trials in the 20th Century.

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