Major depressive disorder (MDD) is the world’s leading cause of disability, affecting some 300 million people worldwide. Traditional treatments, developed in the 1960s and 70s, fail many patients. One in every three patients derives no benefit from medication, and about one of every five people with MDD is classified as having treatment-resistant depression.

At the Icahn School of Medicine at Mount Sinai, scientists are pursuing several lines of research that could open new pathways for treatment of MDD. One of those investigative targets is the interleukin-6 molecule, a protein that mediates communication between cells and plays a role in stimulating inflammation in patients suffering from depression. Researchers at Mount Sinai have found those with depression have abnormally high levels of IL-6. That finding has led to the study of other factors that influence inflammatory pathways and how they may be able to assist neuro-circuits trying to control depression.

Another avenue focuses on the anticonvulsant drug, ezogabine, a potassium ion channel opener approved by the FDA for treating partial seizures, to see if it could have a protective effect for those confronting extreme stress.  In animal studies, ezogabine, when injected or infused, delivered a reduction in symptoms of depression, such as loss of interest, reduced motivation, and inability to feel pleasure. This research indicates ezogabine’s potential to normalize neuron hyperactivity, in effect supplementing the mind’s active resilience mechanisms.

Dennis Charney, the Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai. Credit: Mount Sinai Health System

One of the most promising research targets for depression is the class of receptors in the brain that regulate the neurotransmitter glutamate. Dennis Charney, the Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai, first observed the ability of ketamine—an anesthetic mainly used in veterinary medicine, and also known as the illicit party drug ‘Special K’—to manipulate the glutamate system, and act as an antidepressant. Charney began his groundbreaking research at Yale University, working with John Krystal.

The most commonly prescribed antidepressants, selective serotonin reuptake inhibitors (including Prozac and Zoloft), block reabsorption of the neurotransmitter serotonin by neurons, making more of the chemical available in the brain. The process can ease depression in some patients after several weeks or months. In MDD patients resistant to such treatment, the glutamate system may be much closer to the source of the problem. Chronic stress and depression appear to alter the glutamate receptors and synapses, leading to a loss of synaptic structure.

Ketamine has high affinity for one of the main glutamate receptors in the brain, the NMDA (N-methyl-d-aspartate) receptor. The drug blocks the NMDA glutamate receptor from reuptaking the glutamate it secretes. By restoring a normal level of glutamate, ketamine appears to revive connections between neurons, and can restore neuroplasticity to the brain within a day.

James Murrough, the director of the Mood and Anxiety Disorders Program and Associate Professor of Psychiatry and Neuroscience at the Icahn School of Medicine. Credit: Mount Sinai Health System

Charney and James Murrough, the director of the Mood and Anxiety Disorders Program and Associate Professor of Psychiatry and Neuroscience at the Icahn School of Medicine, have published multiple studies demonstrating the rapid antidepressant effects of ketamine as a new mechanism for treating severe and chronic depression.

“The rapid antidepressant effects of ketamine in patients with severe, chronic, and treatment-resistant forms of this illness may represent a true medical breakthrough,” says Murrough.

Ketamine may be also effective in treating post-traumatic stress disorder, a finding Charney made with Adriana Feder, Associate Professor of Psychiatry at Mount Sinai.

As a result of his research, Charney and his employer, the Icahn School of Medicine at Mount Sinai, hold patents on ketamine’s antidepressant and anti-suicidal effects.

A major pharmaceutical company recently conducted a double-blind clinical study of esketamine, a chemical cousin of ketamine, in treatment-resistant adults. The results, revealed in May, found that a flexibly dosed esketamine nasal spray with a newly initiated oral antidepressant demonstrated a “statistically significant, clinically meaningful rapid reduction of depressive symptoms.”

The U.S. Food and Drug Administration granted esketamine breakthrough therapy designation for treatment-resistant depression in 2013 and will soon consider the esketamine nasal spray for regulatory approval. If it gets a green light from the FDA, esketamine would be the first non-monoamine drug for treating depression, and would represent the first new mechanism of action for an antidepressant since the category of medicine was discovered in the 1950s.

“One hopes through a career in science that you make a discovery that can change the lives of many patients, and it’s very gratifying that we may have made such a discovery with ketamine,” says Charney.

For the millions of MDD sufferers who have found no relief from selective serotonin reuptake inhibitors, these developments could bring hope.

To learn more about how scientists are translating research into life-changing treatments, visit the New Heights in Medicine.