Conference Coverage

Depressed patients respond faster to IV ketamine than intranasal ketamine


AT APA 2022

NEW ORLEANS – New research reveals that patients with treatment-resistant depression who were treated with repeated intravenous ketamine show no significant differences in achieving response or remission, compared with those receiving the intranasal formulation of the drug, esketamine – although fewer treatments appear necessary with the intravenous formulation.

This is one of the first studies to compare the efficacy of IV and intranasal ketamine, and the results give us some indication that, if you treat with IV, you might get a faster response, although at the end, the responses are similar,” said first author Balwinder Singh, MD, of the department of psychiatry and psychology, Mayo Clinic, in Rochester, Minn.

Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota courtesy Balwinder Singh

Dr. Balwinder Singh

The findings were presented at the annual meeting of the American Psychiatric Association.

Commenting on the study, Roger S. McIntyre, MD, underscored that “this is an important study that addresses the priority questions that everyone wants to know – not only for clinical reasons, but economic reasons.” Dr. McIntyre, a professor of psychiatry and pharmacology at the University of Toronto, and head of the university’s mood disorders psychopharmacology unit, said that “there are implications not only for clinical outcomes and cost, but also implementation because IV is obviously more demanding and complicated.”

As intravenous ketamine increasingly gained interest as a rapid-acting treatment for patients with severe, treatment-resistant depression, the introduction of a more convenient intranasal formulation was seen as a welcome improvement and received approval from the Food and Drug Administration in 2019. However, while the approval ushered in more coverage by insurance companies, the treatment can still be expensive. Intravenous ketamine does not have FDA approval.

With a lack of studies in the real-world setting comparing efficacy of the two formulations, Dr. Singh and his colleagues conducted the observational study, evaluating the responses of 62 adults with treatment-resistant depression who had received either up to six IV ketamine infusions of 0.5 mg/kg, infused over 40 minutes, or up to eight intranasal esketamine treatments of 56/84 mg, as approved by the FDA, at the Mayo Clinic Depression Center.

Of the patients, who had a mean age of 47 years, 59 had major depression and 3 had bipolar depression. Among them, 76% (47) received intravenous ketamine and 24% (15) received esketamine, which Dr. Singh noted reflected the higher number of patients included before esketamine received FDA approval. The patients had similar comorbidity profiles, with the intravenous ketamine group having a higher body mass index at baseline.

Overall, the patients all had significant improvement in their depression at the end of the acute phase of 4 weeks, with a mean change in on the 16-Item Quick Inventory of Depressive Symptomatology (QIDS-SR) scale of –8.6 from baseline (P < .001).

The overall remission rate was 38.7% and overall response rate was 58.1%. Those receiving intravenous ketamine had response and remission rates of 57.4% and 42.6%, versus response and remission rates of 60.0% and 26.7% among the esketamine group, which Dr. Singh said were not significant differences (P > .05).

However, the mean number of treatments necessary to achieve response in the intravenous ketamine group was just 2.3 versus 4.6 with esketamine, and the mean number of treatments to achieve remission were 2.5 versus 6.3, respectively (P = .008).

After a multivariate adjustment, the time to response was determined to be faster with intravenous ketamine versus esketamine (hazard ratio, 2.61; P = .05) and the time to remission was also faster (HR, 5.0; P = .02).

“What this means is you would need fewer treatments to achieve a response or remission with IV ketamine, so there could be an acceleration of patients’ antidepressant response,” Dr. Singh explained.

There were no significant differences between the groups in terms of side effects, and most patients tolerated the treatments well.

Dr. Singh noted the limitation of the study is that it was observational and included a small sample size. Nevertheless, when asked which he would choose if starting treatment when insurance was not an issue, Dr. Singh replied: “I would take patient preference into account, but certainly IV seems to have an advantage.”

Dr. Roger S. McIntyre, University of Toronto

Dr. Roger S. McIntyre

Dr. McIntyre noted that, though small, the study’s setting in a real world clinical environment is important.

“Obviously this is observational and not controlled, but the strength is that this involved a real-world cohort of patients and real world applications,” he said. “It’s difficult to have a true comparator head-to-head trial, so that makes this all the more important because it takes into consideration all of the complexities of real world patients.”

Dr. McIntyre emphasized that the study is not “the last word on the story because we need to see a larger sample and replication. But certainly they make an argument that IV ketamine may have an advantage over the speed of onset with intranasal ketamine, which will need to be either replicated or refuted, but it’s a great starting point in the conversation.”


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