A Single Dose of Esketamine May Provide Improvement of Depression Symptoms for Several Weeks

The treatment could be a promising strategy for boosting the efficacy of oral antidepressants, study authors say.

Esketamine is usually administered as a nasal spray.Janssen Pharmaceuticals

People with depression had significant improvement in their symptoms after just one dose of esketamine nasal spray, delivered via intravenous infusion (IV), on top of their existing treatment, according to a study published August 14 in JAMA Network Open.

This study provides promising evidence that a single dose of esketamine could enhance the efficacy of oral antidepressants in treating the challenge of fluctuating antidepressant responses among people with major depressive disorder, wrote the authors.

This study, though small, found a pretty big response in terms of separation from placebo, says Alan Schatzberg, MD, the director of the Stanford Mood Disorders Center and a professor of psychiatry and behavioral sciences at Stanford Medicine in California.

“It suggests that you can give even a single dose on top of a treatment regimen for depression and get a reasonable response — significantly better than a placebo — even with a single injection of esketamine, which goes along with what we see with ketamine,” says Dr. Schatzberg, who was not involved in this study.

What’s the Difference Between Esketamine and Ketamine?

Esketamine nasal spray (sold under the brand name Spravato), taken with oral antidepressant therapy, is approved for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior. While there is evidence of ketamine’s efficacy in treating depression, such use is “off label,” which means it isn’t approved by the FDA for the treatment of depression.

At the molecular level, ketamine has two different orientations: a molecule that points to the left (called “levorotatory”) and a molecule that points to the right (called “dextrorotatory”), according to Mass General Brigham. The drug ketamine is a mixture of the two, while esketamine is the pure levorotatory molecule.

Esketamine is absorbable through certain areas of skin (ketamine is not), and so it can be delivered through an intranasal inhalation, whereas ketamine is delivered via IV infusion.

Can Just 1 Dose of Esketamine Improve Depression Symptoms When Taken With Standard Treatment?

In this pilot clinical trial, investigators set out to evaluate whether a single dose of esketamine delivered through IV (rather than the normal, approved nasal route) could enhance the effectiveness of oral antidepressants in people with MDD.

For the Chinese study, a total of 30 people with MDD with “fluctuating” antidepressant responses were enrolled from August 2021 to January 2022. The median age of the participants was 28.

According to the authors, fluctuating antidepressant response in MDD refers to the re-emergence of initial depressive symptoms or episodes or the onset of a new episode during adequate antidepressant treatment in patients with MDD.

Participants were randomly assigned to receive either esketamine or the control substance, midazolam (Versed), in the double-blind trial — meaning neither the participants nor the investigators knew who received which drug.

Why midazolam? Midazolam injection is used before medical procedures to cause drowsiness, relieve anxiety, and prevent any memory of the event, according to MedlinePlus.

“One issue with studying ketamine and esketamine in terms of double-blind studies, as is true also for psychedelics, is that they give you a kind of an altered state of consciousness and they also can be sedating,” says Schatzberg.

Midazolam is sometimes used as a control in ketamine or esketamine trials (the dose is adjusted to achieve the desired effect) because it can produce a mildly altered state, though it doesn't quite dissociate you the way ketamine does, he says. “It hasn’t been a great control for studying ketamine, but there really isn’t anything better at this point," adds Schatzberg.

Esketamine-treated participants received intravenous esketamine at 0.2 milligrams per kilogram (mg/kg) over 40 minutes, while the control group received intravenous midazolam at 0.045 mg/kg over the same time period.

Esketamine Continued to Improve Fluctuating Symptoms at 4 and 6 Weeks

People who were given esketamine experienced significantly higher response rates at all time points compared with the control group, with a noticeable difference in the first 24 hours. Remission rates were higher in the esketamine group at four and six weeks.

According to the authors, the positive effect and how long the improvement lasted suggest that esketamine could be a promising strategy for boosting the efficacy of antidepressants and improving symptoms of depression.

Drug May Provide Improvement Without People Having to Switch MDD Treatment

“The simplicity and high success rate of esketamine therapy would allow patients to continue using their current antidepressant regimen and avoid adverse effects associated with changes in the medication regimen, for example, unanticipated adverse effects and a reduced willingness to seek treatment due to repeated attempts,” they wrote.

Because the study was small and conducted at a single center, larger and more comprehensive studies are needed to confirm these findings and further explore the safety, efficacy, and mechanisms underlying the interaction between esketamine and oral antidepressants, noted the authors.

“The findings are interesting and may be a signal for more study of medications like ketamine for fluctuating symptoms, but ultimately a lot more research is needed before this is considered for a guideline, for example,” says Smita Das, MD, PhD, a psychiatrist at Stanford Health and a clinical associate professor at Stanford Medicine in California who was not involved in this research.

The Small Study Has Several Limitations

There are several limitations in the design, including the size and the short follow-up, says Dr. Das. “Another drawback is that they base their study on something called fluctuating antidepressant response in MDD. This is a new measure using a visual analog scale, where they ask participants on a scale of 1 to 10 how they feel about their ‘state.’ This is very nonspecific to depression, not a standardized measure, or a validated measure,” she says.

“Finally, in randomizing, 11 of the 15 patients in the control group had previous episodes of depression, whereas in the treatment group it was 4 of 15. This is very important, as the experience of someone with a first depressive episode is very different from someone who has had multiple episodes and a history of trying to manage the episodes, and it may impact how they respond to treatment,” says Das.

More Research Is Needed Before Esketamine Is Recommended for Fluctuating Symptoms

As noted in the paper, esketamine nasal spray has been FDA approved, and shown to be efficacious for treatment-resistant depression. This isn’t a new thing, says Das.

People who have been treated for depression but whose symptoms haven’t improved may have treatment-resistant depression, according to Mayo Clinic.

“It is interesting to consider how to address fluctuating depressive symptoms — which may be distinct from resistant symptoms — that someone may have when already treated for depression, but again, the basis of that study variable is not something that is used in psychiatric research,” she says. In order to produce even more rigorous research around this concept, fluctuating depressive symptoms need to be an agreed-upon concept, adds Das.

Dissociation May Occur With Ketamine and Esketamine

No serious adverse events were observed. Esketamine-treated participants showed a brief period of increased dissociation compared with the control group.

“This to be expected with these drugs,” says Schatzberg.

People treated with esketamine nasal spray commonly experience transient symptoms of dissociation, which can include feelings of detachment from the environment, according to a paper published in International Clinical Psychopharmacology in January 2021. These feelings, which generally peak at 40 minutes and resolve by 90 minutes, can cause anxiety and confusion.

Esketamine Is Administered by Psychiatrists

“This study is unique in that instead of giving esketamine intranasally, they're giving it as a single shot, intravenously,” says Schatzberg. By itself, this drug isn't typically available intravenously outside a clinical trial setting, he says.

To go on esketamine, you need a prescription, and it is administered as a nasal spray by psychiatrists at treatment centers throughout the United States.