Jan. 27, 2025 – After years of limited options, people with hard-to-treat depression finally have a new standalone treatment. The FDA’s latest approval of the nasal spray Spravato (esketamine) CIII marks a major shift in how major depressive disorder is managed, allowing people who have tried at least two oral antidepressants to use the spray on its own – without the need for more medication.
Until now, Spravato, which first hit the market in 2019, was only available with an oral antidepressant. Experts say this expansion could make the treatment more appealing to those who have been hesitant to try it before.
“There’s a certain number of patients who come to us for this treatment who either aren’t on antidepressants, selective serotonin reuptake inhibitors (SSRIs), or really aren’t interested in taking SSRIs, either because they’ve found those to be not helpful, or the depression doesn’t respond, or they don’t tolerate the side effects,” said Robert K. McClure, MD, an associate professor and director of interventional psychiatry at the University of North Carolina Chapel Hill Department of Psychiatry.
The Trouble with Treatment-Resistant Depression
There is significant excitement about the new treatment, as options for people with treatment-resistant depression have been limited, despite the substantial unmet need and public health impact, according to Roger McIntyre, MD, a professor of psychiatry and pharmacology at the University of Toronto and executive director of the Brain and Cognition Discovery Foundation.
Between 30% and 55% of people with depression have treatment-resistant depression, according to McIntyre’s research. It’s often defined as depression that doesn’t improve with at least two different antidepressant drugs.
Treatment-resistant depression is not only common but also more severe, often impairing personal and professional functioning, increasing the use of health care services, and raising the risk of suicidal thoughts and behaviors, he said.
It’s also under-researched. “We have had current treatments for depression going back to the 1950s, but up until recently, we have not had an emphasis looking at how to help people with treatment-resistant depression,” said McIntyre. “Most of the studies have looked at people with non-treatment-resistant depression, and so this is huge.”
When medications don’t relieve depression, the next options might include Spravato, transcranial magnetic stimulation, or electroconvulsive therapy, McClure said.
Electroconvulsive therapy is highly effective, but it’s invasive and can cause memory loss. Most people opt to try Spravato or transcranial magnetic stimulation – which involves stimulating nerve cells in the brain with magnets – first, he said.
Transcranial magnetic stimulation is also time-consuming, requiring treatment five days a week for at least four weeks. With Spravato, you start with two weekly treatments for four weeks. Some people then continue with weekly or twice-weekly maintenance treatments.
How Esketamine Nasal Spray Provides Relief
A study by Johnson & Johnson, the company that makes Spravato, showed that 22.5% of people using esketamine nasal spray achieved remission from major depression in four weeks. Just 7.6% of people using a placebo did.
The history of this drug traces back to the 1960s, when researchers discovered that ketamine, a pain-relieving, mind-altering drug, could curb depression. Ketamine molecules contain two parts: S-ketamine (esketamine), which is like the left hand, and R-ketamine, which is like the right hand, McClure said.
“Standard ketamine is a mixture of the two left- and right-handed versions of the molecule, and the inhaled version is just the left-handed version,” he said.
Exactly how esketamine heals depression isn’t completely understood, but it works differently than SSRIs. Research suggests esketamine works by targeting the neurotransmitter glutamate. Glutamate plays a role in altering brain plasticity – the way brain cells connect and fire together – a hallmark of depression, McIntyre said. Esketamine acts on the N-methyl-D-aspartate receptor (NMDA), a glutamate receptor, which might help reverse processes that alter brain plasticity. Esketamine has been shown to affect glutamate signaling in a matter of days, while oral antidepressants can take weeks.
Spravato isn’t like the nasal spray you use when you have a cold. You get it at a doctor’s office. You spray Spravato into your nostrils according to your health care provider’s directions. Then, you stick around for two hours so they can watch for side effects like high blood pressure, nausea, dissociation, or changes in consciousness, McIntyre said. The spray might also temporarily leave an unpleasant taste in your throat. When the two hours end, someone else must drive you home. You can’t drive until the next day.
Since esketamine has mind-altering properties, it comes with warnings about risks of abuse and misuse. The fact that you can’t take it home is good news for its safety. Research in The American Journal of Drug and Alcohol Abuse shows that when people overdose on ketamine or its analogs, it happens outside medical settings.
“Some people have also wondered whether or not long-term use may predispose gateway activity; in other words, will this prime the person to maybe misuse other drugs?” McIntyre said. “We have not seen that.”
Research also suggests that esketamine nasal spray doesn’t affect thinking skills the way high doses of ketamine do.
What’s Next
Along with treatment-resistant depression, Spravato is approved along with an oral antidepressant for adults with major depressive disorder who have suicidal thoughts or behaviors.
As this drug gets more popular, patients often ask whether it could be used for other conditions that cause depressive symptoms, McIntyre said. “I think that there is an appetite now to know, does it have application in other disorders such as bipolar depression?”
More research is needed to answer those questions. Clinical trials are underway or being planned to test esketamine in postpartum depression, risk of suicide, sleep disturbances, and more.
