Photo: Collage of woman lying in bed taking ketamine pills/Taylor Teeden biospace
The week before Easter 2024, many of the world’s leading ketamine researchers gathered for the annual Ketamine and Related Compounds conference at Oxford’s Blavatnik School of Government. The first day ended with a discussion on the appropriateness of home administration of ketamine for depression, followed by audience voting. A pre-debate vote showed slight opposition to the use of ketamine as a home-administered treatment for depression. However, after exchanging opinions with experts, a subsequent vote resulted in a slight vote in favor.
While this apparent swing in voting may reflect a small change, the fact that the debate even took place is noteworthy in itself. This shows that the ketamine scientific community is actively working on how ketamine’s powerful, fast-acting antidepressant effects can benefit patients while reducing risks.
Depression is a growing health concern, affecting 320 million people worldwide and expected to become the leading cause of global disease burden by 2030. Many patients with depression do not respond adequately to current treatments, and approximately one-third remain treatment-resistant despite multiple treatments. Attempts at treatment.
The advent of ketamine-based treatments has brought hope to people with treatment-resistant depression because of their powerful, immediate effects. However, the effects so far have generally been accompanied by characteristic side effects, such as dissociative psychological experiences and changes in heart rate and blood pressure. This has led regulators to effectively restrict its use by requiring that the only approved ketamine-based depression treatment be taken under proper medical supervision. Ketavon, the Munich-based pharmaceutical company where I work as chief medical officer, has released a drug that uses the antidepressant effects of ketamine without resolving the safety issues that currently prohibit its use at home. We are working on development.
Unique mechanism
To understand where the ketamine field stands today, it is interesting to look back at the history of this groundbreaking drug. Calvin Stevens, a scientist at the Parke-Davis Institute, synthesized this compound in 1962 while he was searching for a new painkiller. Ketamine, originally known as CI-581, quickly caught the attention of researchers. Among them was Edward Domino, a pharmacologist at the University of Michigan who made a serendipitous observation. Ketamine induced a unique dissociative state in human subjects, different from that experienced under traditional anesthesia. This observation laid the foundation for subsequent research into ketamine’s mechanism of action.
Using a combination of animal studies and pharmacological assays, Domino and colleagues suggested that N-methyl-D-aspartate (NMDA) receptors, then an emerging force in neuroscience, were the primary target of ketamine’s effects. revealed strong evidence that Ketamine disrupted glutamatergic neurotransmission by antagonizing this receptor, resulting in its characteristic dissociative and anesthetic effects.
One of the most important advantages of ketamine is its ability to induce anesthesia quickly and reliably, making it particularly suitable for use in emergency situations and during procedures where rapid onset of anesthesia is critical. Furthermore, compared to older anesthetics, induced respiratory depression is minimized.
However, ketamine is not without limitations and potential drawbacks. Hallucinations, delirium, and wakefulness phenomena may occur, especially at high doses and in susceptible individuals. Additionally, concerns have been raised regarding the potential for abuse and the development of tolerance and dependence with chronic use.
If ketamine was used primarily as an anesthetic in a controlled setting, the risk of diversion could be managed. Ketamine’s potential for abuse was first suggested in the late 1970s, when reports of individuals seeking ketamine for recreational purposes began to surface. Ketamine’s unique psychoactive effects attracted certain segments of the population, particularly the burgeoning rave and club scene.
From anesthetics to antidepressants
Ketamine’s psychoactive effects have increased its potential for abuse, but some have found it to have potentially beneficial uses beyond anesthesia. In the late 1990s, intrigued by reports that ketamine rapidly and powerfully affected the mood of patients undergoing anesthesia, John Crystal and colleagues at Yale University explored ketamine’s potential as an antidepressant. We have undertaken a series of groundbreaking research to
Their efforts bore fruit in 2000, when they published the first clinical trial demonstrating that a single subanesthetic dose of ketamine produced rapid and sustained antidepressant effects in patients with treatment-resistant depression. .
Subsequent studies confirmed and further extended these findings, suggesting that ketamine’s antidepressant effects are mediated by its ability to modulate the glutamatergic system in the brain, specifically its antagonism of NMDA receptors. . Until then, the most effective antidepressants worked by modulating monoamine neurotransmission, particularly serotonin and noradrenaline signaling. Importantly, clinically relevant improvements may be seen within days of starting ketamine treatment, rather than weeks later as with standard antidepressants.
Encouraged by these results, academic researchers and pharmaceutical companies are racing to develop ketamine-based treatments for depression, paving the way for a variety of formulations and delivery methods, with intravenous infusions often being used. I cut it open. One of the most notable innovations was the development of Johnson & Johnson’s nasal spray of esketamine, the S-enantiomer of ketamine, which was approved in 2019 and sold under the brand name “Spravato.” . It has several advantages over traditional antidepressants, including a rapid onset of action and the potential to reduce symptoms in patients who have not responded to traditional treatments.
However, Spravato is not without its limitations and caveats, including acute side effects such as dissociation and sedation, and the potential for abuse and misuse. The latter has prompted regulators to impose strict risk mitigation strategies, such as requirements for administration under the supervision of a health care provider in a certified medical setting. Nevertheless, the introduction of Spravato represents an important milestone in the treatment of depression.
Several attempts have been made to balance the efficacy benefits and tolerability issues of ketamine and related compounds to prevent unintended use. One approach, as in Spravato’s case, is to have strict rules about who can administer the drug, where it can be administered, and how patients can be supervised after each treatment. However, this limits his access to one of the most important antidepressant treatments. Examples of other approaches aimed at ensuring the safe use of ketamine-based antidepressants include use of abuse-deterrent formulations, small pack sizes, and pharmacy certification.
Ketabon is pursuing a fundamentally different approach, developing KET01, an oral extended-release ketamine administered as a tablet. Because of the slow uptake of ketamine from the intestine and the extensive metabolism of ketamine in the liver, the amount of ketamine that reaches the systemic circulation is lower than that seen with ketamine-based drugs administered intravenously, intranasally, or immediately. Much less than the quantity. tablet. The resulting low concentrations of circulating ketamine are not sufficient to cause characteristic side effects, such as dissociation, sedation, and increased blood pressure, which are most likely mediated through NMDA receptors.
However, because ketamine is extensively metabolized, relatively high concentrations of metabolites such as norketamine and hydroxynorketamine are found in the circulation after administration of KET01. These metabolites have shown antidepressant-like properties in animal models. Clinical trial data presented by Ketavone at a recent meeting showed that patients with treatment-resistant depression who received KET01 rapidly improved their depressive symptoms, and the improvements were maintained over 3 weeks of treatment and 4 weeks of follow-up. It shows.
These efficacy signals were not associated with increases in dissociation, heart rate, or blood pressure. Ketabon researchers hypothesize that the antidepressant effects of KET01 are driven by ketamine metabolites and that the minimal dissociation may be due to low levels of circulating ketamine.
Emerging data on KET01 suggest that it is indeed possible to achieve rapid improvement in depression without the characteristic side effects of ketamine-based drugs. This improves the tolerability profile and increases the likelihood that ketamine-based depression treatments can be used more widely and safely. If this treatment is ultimately approved, it will be interesting to see how its availability influences the outcome of votes on the home use of ketamine, such as the one recently held in Oxford. right.
Hans Eriksson, MD, PhD, MBA, is Chief Medical Officer of Ketabon and HMNC Brain Health in Munich. Follow him on LinkedIn or learn more about his work at https://www.ketabon.health/ and https://www.hmnc-brainhealth.com/home.
