Esketamine and Deep-Brain Stimulation: New Paradigms for Treatment-Resistant Depression

Esketamine and Deep-Brain Stimulation: New Paradigms for Treatment-Resistant Depression

Two new treatments, esketamine and deep-brain stimulation, can produce substantial symptom relief and lead to considerable improvement in the quality of life for patients with treatment-resistant depression.

5 min read

Decades of research in the field of treatment-resistant depression (TRD) have recently yielded two novel treatment approaches: esketamine* and deep-brain stimulation (DBS). These new treatments can produce substantial symptom relief and lead to considerable improvement in quality of life for patients with this serious condition. Researchers at the Icahn School of Medicine at Mount Sinai have contributed to the advancement of both modalities, and the Department of Psychiatry launched an innovative Treatment-Resistant Depression Program that integrates these options for patients.

The TRD team uses intensive evaluations; past and current symptom and treatment analysis; questionnaires assessing current state of mind; and, if needed, labs, genetic testing, and brain imaging to develop customized treatment recommendations. When appropriate, potential treatment options can include esketamine and referrals to Mount Sinai’s DBS study.

Esketamine: In March 2019, intranasal esketamine was approved by the U.S. Food and Drug Administration (FDA) for patients with TRD. The approval was based in large part on pioneering research from Dennis S. Charney, MD, the Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai and President for Academic Affairs for the Mount Sinai Health System, and his collaborators.  

“As a researcher, you strive to come up with new treatments for the patient, especially in terms of finding answers to the most debilitating diseases,” said Dr. Charney. “To know that you oversaw the early development of an approach that can make a difference in the lives of countless individuals is extremely rewarding.”

James Murrough, MD, PhD, Director of Mount Sinai’s Depression and Anxiety Center for Discovery and Treatment, was actively involved in the research that led to esketamine’s FDA approval. “Depression is one of the largest causes of suffering and disability worldwide,” he said. “The discovery of a new way to treat this condition has the potential to make an enormous impact on patients’ lives.”

  • An alteration in glutamate signaling increases neuroplasticity.

Esketamine is a component of the drug ketamine, which has been used as an FDA-approved anesthetic in medical settings for 50 years. Delivered in the form of a nasal spray, it works on the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor in the brain. Via a series of complex biological processes, esketamine enhances the activity of glutamate in brain regions that are important for mood.

This alteration in glutamate signaling is thought to increase neuroplasticity to 1) allow the brain to cope more effectively with stress, and 2) reverse depression-related brain changes. Since impaired neuroplasticity is linked to depression, enhanced neuroplasticity and “cellular resilience” is thought to ameliorate the patient’s symptoms and lead to recovery.

In contrast to esketamine, conventional antidepressants that have been on the market for decades target the classic monoamine neurotransmitters—serotonin, norepinephrine, and, to a lesser extent, dopamine—and can take weeks, or even months, to work. These drugs are considered ineffective in at least 30 percent of cases.

“Since we know that not all patients will respond to a medication that affects the monoamine system, it is critically important to develop treatments that work on brain targets outside of the monoamine system,” said Dr. Murrough. “If we can identify treatments that work quickly, that represents a major advance for the field. Ketamine is not the end game; with further research, we hope to help usher in a new generation of novel, rapidly acting, and effective treatments.”

Deep-brain stimulation (DBS): DBS has also shown promise as a new therapeutic pathway for TRD. DBS involves implanting an electrode into an area of the brain known as Brodmann Area 25, which is very active in patients with depression. The electrode is connected to a neurostimulator implanted near the collarbone that sends electrical currents to the brain.

Helen Mayberg, MD,** Director of Mount Sinai’s Nash Family Center for Advanced Circuit Therapeutics (C-ACT), led the first trial in 2005 of DBS targeting Brodmann Area 25 for TRD, demonstrating it could have clinical benefit. Dr. Mayberg’s work reached another milestone in late 2019 when she found—based on data collected over eight years—that DBS provides a robust antidepressant effect. The effect is sustained over a long period of time for patients with inescapable depression who have not responded to other treatments.  

  • An electrode is implanted in Brodmann Area 25 in the brain.

“Inevitably patients relapse, so the challenge is not just to get people with TRD out of an episode, but to also keep them out of future ones,” said Dr. Mayberg. “What I find so remarkable about DBS is that it helps patients get better and stay better.”

At Mount Sinai West, two women are currently receiving DBS as part of the first single-site, patient trial involving Brodmann Area 25 funded by the National Institutes of Health. Both were so incapacitated by their depression that they had to stop working despite numerous treatment attempts with medication and even electroconvulsive therapy. With the help of advanced imaging and precision targeting, surgeons recently implanted a neurostimulator in each of their brains.

“The neurostimulator acts like a pacemaker, overriding the signals of depression and working on a continuous basis,” said Martijn Figee, MD, PhD, Associate Professor of Psychiatry, and Neurosurgery, and lead psychiatrist for the patients in the DBS trial. “To date, the patients have improved significantly. They feel more energetic, exhibit better moods, and are working with their therapists to deal with this new state and actively engage in life again.”

Researchers continue to monitor the patients’ facial expressions, speech, and other characteristics on a daily basis using video footage sent from the patients. They also analyze the patients’ daily brain recordings to understand the origins of depression and the mechanisms of recovery via a new prototype system developed by C-ACT. The system, known as Summit RC+S, allows researchers to make simultaneous recordings of brain activity directly from the site of stimulation during active DBS therapy. Dr. Mayberg said she expects Summit RC+S to provide “an unprecedented opportunity to monitor the trajectory of recovery over days, weeks, and months, revealing important new insights into DBS mechanisms and management,” while optimizing clinical outcomes for patients.

*Mount Sinai was involved in the research that led to the development of this new treatment method for treatment-resistant depression and receives financial remuneration from the manufacturer of SPRAVATO. Mount Sinai’s Dean is a co-inventor of patents related to this new treatment method and, as such, receives remuneration through Mount Sinai from the manufacturer. For more information about these financial interests and Mount Sinai’s leadership role in SPRAVATO, please visit (Dr. Murrough does not have a financial interest in SPRAVATO.)

**Dr. Mayberg is a named co-inventor on a novel method for using DBS in a specific region of the brain (the subcallosal cingulate area) as therapy for TRD. This method had been licensed to Abbott Laboratories and Dr. Mayberg has received and is entitled to receive future royalty payments from Functional Neuroscience related to this method. In addition, Dr. Mayberg is a consultant for Abbott Laboratories for the development of other DBS devices for the treatment of neurologic disorders. For this consulting role, Dr. Mayberg does not receive financial compensation.


James Murrough, MD, PhD

James Murrough, MD, PhD

Director of Mount Sinai’s Depression and Anxiety Center for Discovery and Treatment, and Associate Professor, Psychiatry, and Neuroscience

Helen Mayberg, MD

Helen Mayberg, MD

Director of the Nash Family Center for Advanced Circuit Therapeutics