Author Archives: Brina Kim

Since its development in 1962, ketamine has been used primarily as an anesthetic for veterinary procedures. In recent years, however, research investigating its use has extended to psychiatry, with evidence supporting ketamine as a viable treatment for Major Depressive Disorder, colloquially known as depression.

Figure 1. Chemical structure of Ketamine

The most commonly used antidepressant drugs are tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRI). Upon daily administration, these drugs relieve depression, but only after approximately 3- 6 weeks. Moreover, for those with treatment-resistant depression (TRD), SSRIs prove to be of little benefit. Remarkably, current studies suggest that ketamine improves symptoms within 30 minutes, with therapeutic effects for even TRD patients.

An article published in JAMA elucidates the potential of N-methyl-D-aspartate (NMDA) ketamine for the treatment of TRD: in a preliminary study involving eight subjects with depression, Zarate et al determined that a single dose of NMDA ketamine resulted in a rapid but short-lived antidepressant effect. In a subsequent double-blind randomized clinical trial, subjects received intravenous infusions of ketamine hydrochloride or midazolam as placebo. The participants used the Hamilton Depression Rating Scale (HDRS) to measure the changes in drug efficiency. As seen in the linear mixed model, in Figure 2, the difference between ketamine and placebo treatment over 9 points from baseline to 7 days were examined with standard error. Within 110 minutes after the injections, participants receiving ketamine showed significant improvement in depression compared to subjects receiving placebo (with P<0.05).

Figure 2. Changes in the 21-item Hamilton Depression Rating Scale (HDRS)

The implications from this study and the many other breakthrough studies have not gone unnoticed. The development of chemical variations of ketamine has shown that the drug is a powerful tool that can allow people to live life to the fullest potential. In fact, on March 5th, 2019, the Food and Drug Administration (FDA) approved Esketamine, a nasal spray formulation derived from ketamine, for TRD. Targeting the brain’s glutamate pathway, Esketamine is the first drug in thirty years to be approved with a new mechanism of action for treating depression. Of course, the FDA approval of Esketamine does not negate the lingering caveats and concerns relating to its abuse. Nonetheless, even as studies continue to investigate Esketamine’s adverse effects, many physicians remain optimistic that it may become “the biggest breakthrough in depression treatment since Prozac.”

Figure 3. Esketamine, which will be marketed under the trade name, Sparavato

In the following video, Dr. J. John Mann at Columbia University highlights the importance of the approval of Esketamine and the potential risks involved.

-Brina

Throughout history, both natural and synthetic opioid drugs have been considered popular therapy for chronic pain. However, their role as effective painkillers has been challenged by the potential for desensitization and addiction. Currently, the United States (U.S.) and Canada face an opioid crisis of epidemic proportions, with overdoses and related deaths attributed to prescription opioids (POs) as well as illicit, synthetic opioids.

Fig 1. Chemical Structures of Opioid

This epidemic arose partly from an extensive history of over-prescribing practices. Many studies have suggested a link between PO availability and related mortality in both Canada and the U.S. Fortunately, the rise in reports connecting PO availability to mortality has been followed by a decrease in the number of opioid prescriptions, as seen in Figure 2 (2016 to 2017).  

Figure 2. The Number of people prescribed an opioid. Source: CIHI

In the U.S., heroin, compared to any other single drug, is responsible for at least twice as many deaths. Alarmingly, in 2017, the number of people who have used heroin in their lifetime was over 5 million (seen in Figure 3).

Figure 3. Statistics of people in the U.S. who have used heroin in their lifetime from 2019- 2017. Source: National Survey on Drug Use and Health

Across Canada and the U.S., current treatment for opioid use disorder predominantly rests on replacement therapy with methadone or buprenorphine, which can help reduce withdrawal symptoms and maintain abstinence. Systemically, the reinforcement of regulations for PO has been attempted in parallel with the development of anti-abuse technology.

One promising anti-abuse strategy focuses on vaccination. Interestingly, one of the earliest attempts to reduce the misuse of psychoactive substances was reported in the 1970s, when a conjugate vaccine containing morphine-like hapten was tested in animal subjects. At the time, however, the emergence of Methadone, a pharmacotherapeutic for opioid ceased further development of this vaccine. Although drug conjugate vaccine research re-emerged in the 1990s, this time focused on cocaine and nicotine, limited success in human trials challenged the clinical value of this approach to substance abuse treatment—until now.

Learning from the failures of past attempts, a team of chemist and immunologists at The Scripps Research Institute recently developed an opioid vaccine candidate that neutralizes doses of heroin without any known side effects. In essence, the vaccine stimulates the immune system to produce antibodies that bind to heroin and block it from reaching the brain thus eliminating the euphoric high. 

Their study was conducted on non-human primates, specifically four monkeys that were each given three doses of the vaccine. Following vaccination, the treatment countered heroin’s effects, and it continued to provide some degree of protection for more than eight months. Given that the components of this vaccine either have been approved by the FDA or have passed safety tests previously, the researchers believe that this candidate will prove safe in humans. In order to confirm, their next step involves licensing the vaccine to an outside company and establishing a partnership for future clinical trials. As we continue refining this vaccine against heroin, its progress can pave the road for the development of even more vaccines for other opioid synthetics, thereby expanding our approaches to substance abuse treatment.

-Brina