Treatment-Resistant Depression (TRD): Esketamine Therapy

For people in a major depressive crisis, time is of the essence. Oftentimes, a few hours can mean the difference between life and death. Enter esketamine, the first new drug for major depressive disorder (MDD) that may provide rapid symptom relief of suicidal thoughts in just one full dose.

Esketamine (brand name Spravato) was FDA approved in 2019 for adults with treatment-resistant depression (TRD) who have tried other antidepressant drugs without relief. Thankfully, the medication is covered by Medicare and most insurance schemes. In 2020, the National Alliance on Mental Illness (NAMI) blogged about this amazing drug, calling it the only approved medication that has shown a reduction in depressive symptoms within 24 hours of use. Indeed, esketamine is a game-changer.

In this article, we will be exploring this life-changing drug: how it works, its benefits and limitations, and its impact on families and communities. You’ll also get an up-close look at esketamine through the eyes of a research coordinator trained in clinical psychology and studying major depression, Ms. Meenakshi Rozenstrauch, MS, who was involved in one of the esketamine clinical trials.

How Does Esketamine Treat Major Depression?

Major Depressive Disorder (MDD) affects approximately 300 million people worldwide, and although current treatment options can be helpful, it often takes weeks or months for patients to show improvement if any. Approximately one-third of major depression patients do not respond adequately to current antidepressant treatments. That’s where esketamine comes in—a much-needed medication for treatment-resistant depression.

Esketamine's ability to treat depression employs a different mechanism than routine medications. Most antidepressants work by raising levels of neurotransmitters—brain chemical messengers that aid transmission between brain cells. It is believed that having more of the neurotransmitters improves communication between brain cells and therefore mood. The difference is that whereas other medications raise levels of neurotransmitters such as serotonin, norepinephrine, and dopamine, esketamine increases levels of glutamate, which is the most plentiful neurotransmitter in the brain, thereby causing a higher effect on more brain cells.

Most amazingly, it was found to not only address serious depression symptoms immediately but also actually help reduce the frequency of suicidal thoughts and repair scarred neurons very quickly, thereby restoring some important previous, normal neuronal connections. Long-term safety is still being investigated.

What Was It Like for Participants in The Clinical Trials?

After expressing interest and agreeing to participate, eligible individuals were enrolled in the trial, M.Rozenstrauch explained. They were then randomly assigned either the investigational drug or an inactive compound (one that looks like the active drug but has no effect, called a placebo). Placebos are used by researchers to determine if any differences between study groups are due to the active medicine or the participants' perceptions. Participants who were assigned the investigational drug started off with a higher dose and then were tapered down to a lower maintenance dose over time. The participants were only allowed to take the investigational drug while in the clinic, under the supervision of the medical staff and study team, so that any reactions could be managed.

As with all investigational drugs, unforeseen reactions were a possibility, so all participants were monitored for several hours, and issues were addressed with rapid medical care if needed. Uncomfortable dissociation (out-of-body experience), or nausea were two noted reactions to the drug. The study team ensured that participants’ vitals were stable and that they were able to walk unaided, and helped provide them with certified car services to take them home after discharge so they didn’t have to operate a vehicle. As an additional safety measure, after they left the clinic, the participants could call the medical team directly at any time on a 24-hour call line with any questions or concerns.

However, M.Rozenstrauch noted that not everyone who would’ve liked to participate was eligible. There was a careful screening process that each person had to go through, where medical conditions were checked and their willingness to adhere to study activities according to the schedule was ensured. An independent oversight committee called the IRB had to review the study plan and give approval for the study before any activities began.  

What Are The Benefits and Limitations of Esketamine Therapy?

For a deeper understanding of the impact of esketamine therapy, we talked further with  M.Rozenstrauch about her experiences managing one of the esketamine clinical trials while at The Medical Research Network, LLC (MRN) founded by Columbia University psychiatrist Michael R. Liebowitz, MD. She shared her personal experiences as a clinical coordinator as well as some of the wonders and limitations of esketamine that she observed.

M.Rozenstrauch worked with patients with severe depression at The Medical Research Network, LLC in New York. She saw firsthand the terrible impact that major depressive disorder (MDD) had on previously happy and successful lives. Adults suffering from this illness generally find even the smallest tasks, such as maintaining basic hygiene like showering, to be overwhelming. Jobs are lost, relationships are torn apart, and the bitterness of isolation and loneliness seeps in. Sometimes suicide is an unfortunate outcome. Little surprise that the investigational drug with its near-rapid effects got her attention.

One major esketamine benefit she noted was that within a few short hours of their first dose, participants would usually progress from hardly being able to get out of bed to planning visits and events with loved ones. The result was nothing short of astonishing. She stated that during the trial, it was clear which people got the inactive substance and which got the active drug because the reactions were so obviously different. For example, one person who had very strong suicidal thoughts quickly improved and was able to return to their previous artistic profession while taking the lower dose. Another person entered the study not even being able to cook for their grandchildren, but after weaning to the lower dose, within a few months, they were out in the community and had enrolled in a graduate degree program. “They exclaimed to me, ‘this drug opened the door for me to get my life back!’”, M.Rozenstrauch stated.

On the other hand, there were also limitations involving the drug. Some people in the study showed no immediate reaction at all with no improvements in their symptoms. M.Rozenstrauch noted that some participants did well initially but could not adjust to the lower dose, and some did not see improvement in their symptoms over the long term. She reiterated that because of the unique individuality of each participant, while the drug made a dramatic difference for many, there were still some that did not benefit as much as others. She also noted that the drug may generate a strong psychedelic response for some people and may have unacceptable side effects, therefore careful management in a controlled medical office with a healthcare provider’s supervision is required.

What Impact Might Esketamine Have on Families and Communities?

M.Rozenstrauch noted that there are many communities that struggle with major depression and might really benefit from esketamine, such as the LGBTQ and other historically marginalized communities.

She agreed that the benefits to families and the community as a whole could be indirect and long-term, such as people returning to their previous jobs, enriching the community with their talents, and reducing the burden of care on the local health system and community support services.

If you would like more information about ongoing research on the long-term safety of esketamine, visit clinicaltrials.gov.

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