Yale School of Medicine Expert John H. Krystal Awarded 2023 Rhoda and Bernard Sarnat International Prize in Mental Health for Discovery of Novel Antidepressant Mechanism

On October 8, Dr. John H. Krystal, Chair of the Department of Psychiatry at Yale School of Medicine, was honored with the 2023 Rhoda and Bernard G. Sarnat International Prize in Mental Health by the National Academy of Medicine (NAM).

This honor is shared by Krystal with her colleagues, Dr. Dennis Charney and Dr. Husseini Manji. The award recognizes the three individualsThe rapid antidepressant effects of ketamine were discovered, and its efficacy in treatment-resistant depression was confirmed.It is precisely based on this discovery that its derivative, esketamine, became the first antidepressant with a novel mechanism of action approved by the FDA in over 50 years.

Dr. John H. Krystal stated, “This discovery is highly significant, as it has improved the lives of so many people.” This work originated at Yale University and the VA Connecticut Healthcare System, a unique community dedicated to neuroscience and psychiatry.

The Rhoda and Bernard Sarnat International Prize in Mental Health, awarded annually by the U.S. National Academy of Medicine, was established in 1992 through an endowment fund created by Rhoda and Bernard Sarnat. The prize recognizes individuals, groups, or organizations that have achieved outstanding accomplishments in advancing the basic science, clinical application, and public policy of mental health. It includes a medal and a cash award of $20,000.

These achievements have led to advances in the understanding, etiology, prevention, treatment, or cure of mental illness, or to the promotion of mental health. As defined by the nomination criteria, the field of mental health encompasses neuroscience, psychology, social work, nursing, psychiatry, and advocacy. Each year, a selection committee appointed by the Non-Aligned Movement reviews nominations based on selection criteria that reflect the ideals of Rhoda and Bernard Sarnat.

The findings of Dr. John H. Krystal, Dr. Dennis Charney, and Dr. Husseini Manji were published in the journal *Biological Psychiatry* in 2000. Their study demonstrated that ketamine, as a rapid-acting antidepressant, can improve symptoms within hours of administration and induce high clinical response rates within 24 hours after a single dose. The researchers also found that ketamine can be used to treat treatment-resistant depression.

This represents a novel antidepressant mechanism, distinct from traditional antidepressants that require several weeks of treatment to elicit a clinical response.

Ketamine is a strictly controlled psychotropic anesthetic agent that has long been used clinically as an inhalational anesthetic. It was not until the early 21st century that the discoveries of three scientists unveiled its significant applications in the field of antidepressant therapy.

Ketamine acts as an NMDA receptor antagonist in the brain, directly targeting the glutamatergic nervous system to enhance synaptic plasticity, reverse depression-induced synaptic damage, and achieve rapid therapeutic effects. Within hours of administration, it can alleviate negative symptoms such as depressed mood and low self-esteem, reduce suicidal ideation, and demonstrate efficacy in treating treatment-resistant depression. However, its clinical application is significantly limited by adverse effects, including dissociative hallucinations.

In recent years, a growing body of research has demonstrated the efficacy of ketamine in treating treatment-resistant depression, thereby accelerating its clinical approval.

By mimicking ketamine’s blocking effect on NMDA receptors, scientists developed esketamine, the dextrorotatory enantiomer of ketamine. On March 5, 2019, Spravato nasal spray, developed by Johnson & Johnson, received expedited approval from the U.S. FDA for the treatment of treatment-resistant depression, with a voting result of “14:2.”

In a press release issued by Johnson & Johnson, it was stated that “Spravato reduced the risk of relapse in patients with treatment-resistant depression by 51% compared to those who maintained their regimen of placebo and oral antidepressants.”

As the first antidepressant with a novel mechanism of action approved by the FDA in over 50 years, Spravato has also faced considerable skepticism. According to reports, two members of the FDA advisory committee who voted against approving esketamine expressed concerns about the drug’s side effects and its potential for abuse. Some researchers have publicly voiced worries that long-term use of Spravato may lead to adverse outcomes such as addiction.

According to the medical media outlet STAT, two of the five Phase III trials yielded positive results. One was a randomized trial involving adults under the age of 65 with treatment-resistant depression. After one month of pharmacotherapy, approximately 70% of patients experienced remission of depressive symptoms, while the rate in the placebo group was slightly lower but still exceeded 50%. The other was a maintenance-of-effect study, in which participants who had responded to Spravato in a short-term study were randomized to either continue treatment or switch to placebo.

Therefore, the FDA imposes strict controls on Spravato—it “must be used in conjunction with an oral antidepressant and is indicated only for adult patients with treatment-resistant depression.” Furthermore, the FDA mandates that administration take place exclusively in certified healthcare facilities. In other words, patients must regularly visit these facilities to receive the medication under medical supervision following physician evaluation.

The FDA has stated that Spravato may impair attention, judgment, thinking, reaction speed, and motor skills. The most common side effects observed in clinical trials included dissociation, nausea, and increased blood pressure. To mitigate the adverse effects of these side effects, healthcare facilities must monitor patients for at least two hours after administration until they are deemed safe to leave.

In August 2020, the drug’s indications were expanded to include patients with major depressive disorder at risk of self-harm or suicide. The full course of treatment consists of twice-weekly administrations for four weeks, followed by an assessment of therapeutic benefit to determine whether continued treatment is necessary.

In December 2019, the European Commission authorized Spravato, in combination with other antidepressant medications, for the treatment of adult patients with treatment-resistant major depressive disorder. On February 8, 2021, the indication was expanded to include use in combination with oral antidepressants for the rapid reduction of depressive symptoms in adults experiencing a major depressive episode.

On April 20 this year, Janssen China, the pharmaceutical subsidiary of Johnson & Johnson in China, announced that its product Spravato (esketamine hydrochloride nasal spray) had received marketing approval from the National Medical Products Administration of China. It is indicated for use in conjunction with an oral antidepressant to alleviate depressive symptoms in adult patients with major depressive disorder who are experiencing acute suicidal ideation or behavior.

The report states that Sukailang is the first antidepressant approved in China with a novel mechanism of action and route of administration.

In China, the lifetime prevalence of major depressive disorder among adults is 3.4%, and suicidal ideation or behavior is one of the core symptoms of depression. More than 50% of Chinese patients with depression have experienced suicidal ideation, and 23.7% have engaged in suicidal behavior. Current treatment options have a slow onset of action, leaving patients and their families under constant pressure from the potential risk of suicide associated with depression.

According to an announcement by Janssen China, two pivotal global Phase III clinical trials supporting the marketing authorization approval demonstrated that, in adult patients with depression accompanied by acute suicidal ideation or behavior, Spravato® combined with standard of care (oral antidepressants) resulted in clinically meaningful and statistically significant improvements in depressive symptoms as early as 24 hours after the first dose, compared with placebo plus standard of care. Furthermore, benefits in the improvement of depressive symptoms were observed within four hours after the initial administration.

These two studies also demonstrated that Spravato® provided sustained improvement in depressive symptoms from 4 hours to 25 days after the initial dose, with a higher proportion of patients achieving clinical remission (MADRS total score ≤12) compared to placebo nasal spray plus standard treatment.