People with depression experience significant improvement in their symptoms after just one dose of esketamine nasal spray, given by intravenous (IV) infusion, on top of their existing medication, according to a study published Aug. 14 in The Open JAMA Network.
This study provides promising evidence that a single dose of esketamine can enhance the efficacy of oral antidepressants in treating fluctuating antidepressant response challenge among people with major depressive disorder, write the authors.
This study, although small, found a sizable response in terms of separation from the placebo, says Alan Schatzberg, MD, director of the Stanford Mood Disorders Center and a professor of psychiatry and behavioral sciences at Stanford Medicine in California.
“This shows that you can give even one 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 is in line with what we saw with ketamine,” said Dr. Schatzberg, who was not involved in this study.
What is the Difference Between Esketamine and Ketamine?
Esketamine nasal spray (sold under the brand name Spravato), used in conjunction 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. Despite evidence of ketamine’s efficacy in treating depression, such use is “off-label,” meaning it is not approved by the FDA for the treatment of depression.
At the molecular level, ketamine has two distinct orientations: a left-facing molecule (called “levorotatory”) and a right-facing molecule (called “dextrorotatory”), according to Mass General Brigham. The drug ketamine is a mixture of the two, whereas esketamine is a pure levorotatory molecule.
Esketamine can be absorbed through certain areas of the skin (ketamine is not), so it can be given by intranasal inhalation, whereas ketamine is given by IV infusion.
Can Just 1 Dose of Esketamine Improve Depression Symptoms When Taken With Standard Medication?
In this pilot clinical trial, researchers began evaluating whether a single dose of esketamine given by IV (rather than the normal approved nasal route) might increase the effectiveness of oral antidepressants in people with MDD.
For the Chinese study, a total of 30 people with MDD with a “fluctuating” antidepressant response were enrolled from August 2021 to January 2022. The mean age of participants was 28 years.
According to the authors, fluctuating antidepressant response in MDD refers to the reappearance of symptoms or the initial depressive episode or the onset of new episodes during adequate antidepressant treatment in patients with MDD.
Participants were randomly assigned to receive esketamine or a control substance, midazolam (Versed), in a double-blind trial – meaning neither the participants nor the researchers know who received the drug.
Why midazolam? Midazolam injection is used before medical procedures to induce drowsiness, relieve anxiety, and prevent memory of events, according to MedlinePlus.
“One problem with studying ketamine and esketamine in terms of double-blind studies, as is also true for psychedelics, is that they give you a kind of altered state of consciousness and they can also be anesthetizing,” Schatzberg said.
Midazolam is sometimes used as a control in trials of ketamine or esketamine (the dose is adjusted to achieve the desired effect) because it can produce a slightly altered state, although it doesn’t segregate you quite as much as ketamine does, he says. “It’s not a great control for studying ketamine, but there really isn’t a better one right now,” Schatzberg added.
Esketamine-treated participants received intravenous esketamine at 0.2 milligrams per kilogram (mg/kg) for 40 minutes, while the control group received intravenous midazolam at 0.045 mg/kg over the same time period.
Esketamine Continues to Improve Fluctuating Symptoms at 4 and 6 Weeks
People who were given esketamine experienced significantly higher response rates at all time points than the control group, with a marked 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 effects and how long improvements last suggest that esketamine could be a promising strategy for increasing the efficacy of antidepressants and improving depressive symptoms.
Medication Can Provide Improvement Without People Having to Switch MDD Medications
The simplicity and high success rate of esketamine therapy will allow patients to continue on their current antidepressant regimen and avoid the side effects associated with a change in drug regimen, for example, unexpected side effects and reduced willingness to seek treatment due to repeated attempts. ” they wrote.
Because this study was small and conducted in a single center, larger and more comprehensive studies are needed to confirm these findings and further explore safety, efficacy, and the mechanisms underlying the interaction between esketamine and oral antidepressants, the authors wrote.
“These findings are exciting and may signal for further study of drugs like ketamine for fluctuating symptoms, but ultimately more research is needed before these are considered guidelines, for example,” said Smita Das, MD, PhD, a psychiatrist at Stanford Health and clinical associate professor at Stanford Medicine in California who were not involved in this study.
Small Study Has Some Limitations
There were some limitations to the design, including size and short follow-up, said Dr. Das. “Another drawback is that they based their study on something called the fluctuating antidepressant response to MDD. This is a new measure that uses a visual analogue scale, in which they ask participants on a scale of 1 to 10 how they feel about their ‘state’. It is not very specific for depression, not a standardized measure, or a validated measure,” he said.
“Finally, in the randomization, 11 of 15 patients in the control group had a prior depressive episode, whereas in the treatment group it was 4 of 15. This is very important, because a person’s experience with a first depressive episode is very different. from someone who has multiple episodes and a history of trying to manage episodes, and that can affect how they respond to treatment,” says Das.
More Research Is Needed Before Esketamine Is Recommended for Symptomatic Fluctuations
As noted in the paper, esketamine nasal spray is FDA approved, and has been shown to be efficacious for treatment-resistant depression. This is nothing new, says Das.
People who have been treated for depression but whose symptoms have not improved may have treatment-resistant depression, according to the Mayo Clinic.
“It’s interesting to consider how fluctuating depressive symptoms – which may be different from resistant symptoms – that someone might have while already being treated for depression, but again, that baseline of research variables is not something used in psychiatric research,” he said. To produce more rigorous research around this concept, fluctuating depressive symptoms need to become an agreed upon concept, Das added.
Dissociation Can Occur With Ketamine and Esketamine
No serious side effects were observed. Esketamine-treated participants showed brief periods of increased dissociation compared to the control group.
“This is to be expected with these drugs,” says Schatzberg.
People treated with esketamine nasal spray generally experience temporary symptoms of dissociation, which can include feelings of detachment from surroundings, according to a paper published in International Clinical Psychopharmacology in January 2021. These feelings, which generally peak at 40 minutes and dissipate by 90 minutes, can create anxiety and confusion.
Esketamine Is Administered by a Psychiatrist
“This study is unique in that instead of giving esketamine intranasally, they gave it as a single injection, intravenously,” said Schatzberg. By itself, these drugs are usually not available intravenously outside of clinical trial settings, he said.
To use esketamine, you need a prescription, and it is given as a nasal spray by psychiatrists in treatment centers across the United States.
#Esketamine #Enhances #Efficacy #Oral #Antidepressants #Treating #Fluctuations #Depressive #Symptoms
