ENC Health Currents: New Treatment In Development For Depression, Suicidality

Jun 6, 2018

Esketamine is an enantiomer of the ketamine molecule. It's a glutamate receptor modulator, thought to help restore synaptic connections in brain cells in people with major depressive disorder.
Credit Creative Commons

Researchers are developing a nasal spray formulation of esketamine, part of the ketamine molecule, that can rapidly treat depression and suicidal thoughts. 

Doctors use ketamine for pain relief and as an anesthetic.  Some people use it recreationally as a hallucinogenic drug.  Now, researchers are interested in an experimental treatment using part of the ketamine molecule to develop the first-ever drug for people suffering from suicidal ideation.

"Depression is the psychiatric disorder that is most commonly associated with suicide and there are no treatments for patients who are in a suicidal crisis."

Dr. Carla Canuso is the senior director of Jannsen Research & Development, a pharmaceutical company of Johnson & Johnson.  The company started working with esketamine in the mid-2000's with a series of studies to develop appropriate dosing and formulation.   They also looked at the effects in patients with treatment resistant depression.  Now, they’re developing a nasal spray formulation of esketamine that shows a rapid reduction of depressive symptoms in only a few hours.    

"This is distinct from our currently available anti-depressants because it's working through a different set of neuro transmitters than our typical anti-depressants that are currently available and have been available for the last 50 years."

The esketamine nasal spray formulation is in the family of new drugs called glutamate receptor modulators, Canuso said.

"So the glutamate modulators work by increasing glutamate release and that is thought to result in a rapid action on synaptic plasticity.  In other words, it's able to alter the function and connectivity of brain cells, you know, within a very short time period to strengthen the connection and promote better cross-talk between the neurons."

Because of its rapid effect, researchers began to ask if this could be used as a treatment for suicide.   In 2014, Canuso said they conducted a proof-of-concept study of 68 participants with treatment resistant depression who were presenting to the emergency room in a suicidal crisis. 

"Normally what we do for patients who are acutely suicidal is hospitalize them and provide a safe environment and close observation while we initiate anti-depressant therapy and other psychotherapy. 

However, standard anti-depressants often take four to six weeks to show their full effect.   

"In the case of the study, we were able to then also randomize them to receive either the intranasal esketamine or placebo, on top of their standard of care and then compare the two treatments, you know, in the context of standard of care.  And what we found is of course that we were able to rapidly reduce the depressive symptoms and also rapidly reduce some measures of suicidal ideation within four hours."

If approved, the nasal spray formulation would be one of the first new approaches to treat major depressive disorder available to patients in the last 50 years.  In response to the findings, the U.S. Food and Drug Administration granted Breakthrough Therapy designation for the esketamine intranasal spray, which fast tracks the development and review processes. 

"The goal of our treatment will be to bring the symptoms under rapid control but also to bridge that gap that normally takes for an anti-depressant to exert its full effect."  

The esketamine nasal spray would also be the first medication that can help people presenting symptom of suicidal ideation.  For Dr. Phillip Ninan, affiliate professor of psychiatry at East Carolina University's Brody School of Medicine in Greenville, the drug can't come soon enough.    

“For us to have a treatment in our hand that would have a fairly rapid onset of effect would really dramatically change the delivery of care in people struggling with depression and suicidal ideation and behavior.”

Ninan also serves on the National Board of Directors for the non-profit American Foundation for the Prevention of Suicide.  He said mortality is a significant issue in people with depression.  In the past year, about 45,000 people in the United States died by suicide.

“Given that… it would be the first and only treatment that is available for people in this situation, I think not providing it would be a potential problem.  And so clinicians and, you know,  East Carolina University, the Department of Psychiatry will be doing everything possible to be able to deliver the care that would provide the health benefits for people who are suffering from illnesses like depression.” 

There are side effects of esketamine including dizziness, nausea and dissociative symptoms.  Patients would also have to go to a doctor’s office or hospital each week or every other week to receive the treatment until the standard anti-depressants take effect.

Esketamine nasal spray is on the path for approval by the FDA and the European Health Authority late this year for treatment resistant depression.  Canuso said they hope to file esketamine nasal spray for the treatment of suicidal ideation in the beginning of 2020 once all the studies are completed.  

“Currently we are conducting two global studies, 20 countries over four continents are participating.  And we're about half way done [with] the study in terms of patient enrollment.  So far, we've studied over 200 patients in these studies and we hope that the results are consistent with our preliminary findings that we recently published.

Canuso was the lead author in a peer-reviewed study on the efficacy of intranasal esketamine for rapid reduction of major depressive symptoms.  The study was published in April in the American Journal of Psychiatry.