IV Ketamine: A Possible ‘Trajectory of Improvement’ in Severe Depression

Intravenous ketamine may hold potential advantages over esketamine spray (Spravato) for improving severe depression in a clinical setting, a comparative analysis suggested.

In the retrospective study of 129 patients who received IV ketamine and 81 who received intranasal esketamine, those on IV treatment saw slightly larger — yet not significantly so — improvements in Montgomery Åsberg Depression Rating Scale (MADRS) scores after eight treatment sessions (estimated score difference 2.15, 95% CI -0.06 to 4.37, P=0.06), reported Sina Nikayin, MD, of Yale School of Medicine in New Haven, Connecticut, and colleagues.

Certain secondary outcomes did statistically favor IV ketamine versus esketamine spray, however, they said in a research letter in JAMA Psychiatry.

For example, when Nikayin’s group only included MADRS scores from the first six treatment sessions — the average that patients completed — those on IV ketamine had a 2.49-point (95% CI 0.01-4.98, P<0.05) higher score than those on esketamine.

And IV ketamine yielded higher Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) scores after both the full treatment course (1.59, 95% CI 0.24-2.94, P=0.02) and when just looking at the first six sessions (1.64, 95% CI 0.08-3.19, P=0.04).

The authors concluded that their findings “suggest a trajectory of improvement in favor of intravenous ketamine, although this should be interpreted with utmost caution” because of the study limitations, including its retrospective nature and lack of randomization.

Esketamine nasal spray was FDA approved in 2019 as a concomitant treatment with an oral antidepressant for treatment-resistant depression. However, the treatment has come with several barriers to access, including difficulty with insurance coverage.

IV racemic ketamine, while widely studied for years, is not currently FDA approved for depression. It is approved as an anesthetic, but is often used as an off-label depression treatment. The “Yale Interventional Psychiatry Service (IPS) provides both intravenous ketamine (0.5 mg/kg over 40 minutes) and intranasal esketamine (56 or 84 mg),” the authors explained.

There weren’t any significant differences between the two treatments in regards to average suicidal ideation scores measured by MADRS item 10 (3.03 to 1.33 for ketamine vs 2.64 to 1.26 for esketamine).

There also weren’t any differences in response rates (37.8% vs 36.0%). Likewise, 29.6% of ketamine-treated patients achieved severe depression remission versus 24% of esketamine-treated patients. There were still no between-group differences when restricted to only a subgroup of 46 patients who were ages 65 and older; this age group saw average response and remission rates of 32.6% and 30.4%, respectively, without between-treatment differences.

“There has been a lot of speculation about potential differences in the effects of these treatments,” Nikayin told MedPage Today in an email. “There are multiple factors that could cause a difference, including dosing, route of administration, the role of arketamine, and even non-specific and psychological effects.”

Because of this, he and his colleagues were not surprised to see these differences in regards to some of the secondary outcomes, Nikayin stated. “We were also not surprised that response and remission were relatively similar, as we see both treatments work very well in clinical practice every day,” he said.

“When administered in an evidence-based manner and with rigorous clinical standards, [both treatments] can provide relief to patients suffering from depression who have failed to respond to other treatments,” Nikayin highlighted.

The authors noted that these response and remission rates were somewhat lower than previous reports, but were still within the range reported in prior data. They explained that this could be because all patients included were treated at IPS, a tertiary referral center that often treats patients with more severe and treatment-resistant depression.

Patients at IPS can opt for either treatment type and are provided with similar support in the same physical space, the authors said. On average, study patients participated in 6.44 acute sessions and 84.8% completed the entire prescribed course.

The majority of study patients were female (60%), most were white (94.8%), and three-fourths had private insurance. Nikayin’s group acknowledged that the patient population was not representative of the general population, and speaks to great accessibility issues with ketamine-based treatments.

“Identifying and addressing factors related to access is paramount and requires further attention,” they said.

They also stated that future studies should evaluate the two treatments in a randomized trial. “While our study suggests there may be some differences between these treatments, we need further studies to better understand these potential differences, at which point we may be able to personalize treatments better for each patient and choose the best modality of treatment for them,” Nikayin said.