IV Esketamine, Ketamine Equally Effective for Resistant Depression

Nancy A. Melville

April 03, 2020

Intravenous (IV) esketamine is as safe and effective as IV ketamine for patients with treatment-resistant depression, new research suggests.

"Our study was the first randomized clinical trial directly comparing ketamine and esketamine in treatment-resistant depression," senior investigator Lucas C. Quarantini, MD, PhD, Division of Psychiatry, Professor Edgard Santos University Hospital, Federal University of Bahia, Salvador, Brazil, told Medscape Medical News.

The findings showed that esketamine was not inferior to ketamine in remission of depressive symptoms 24 hours after a single IV dose; and the two treatments had similar side effect profiles, Quarantini said.

Furthermore, "our results showed that only the number of treatment failures was an important factor for the remission of symptoms," he added.

The findings were scheduled to be presented this month at the Anxiety and Depression Association of America (ADAA) Conference 2020, along with publication in the Journal of Affective Disorders. However, the ADAA conference was cancelled in the wake of the coronavirus pandemic.

More Treatment Options

The randomized, double-blind noninferiority trial compared IV racemic ketamine and esketamine, two formulations of the glutamate NMDA receptor modulator drug. It included 63 participants (61.9% women; mean age, 47 years) with treatment-resistant major depressive disorder, as determined by DSM-5 criteria.

Participants were enrolled between March 2017 and June 2018 and randomized to receive a single subanesthetic dose of racemic ketamine (0.5 mg/kg; n = 29) or esketamine (0.25 mg/kg; n = 34) for 40 minutes.

Results showed esketamine to be noninferior to ketamine as determined by the Montgomery-Asberg Depression Rating Scale (MADRS).

At 24 hours following infusion, 24.1% of the ketamine group versus 29.4% of the esketamine group showed remission of depression. The difference of just 5.3% confirmed noninferiority.

Although ketamine showed a tendency to have a longer-lasting antidepressant effect compared with esketamine, the difference did not reach statistical significance and should be evaluated in future studies, the investigators note.

Both treatments were safe and well tolerated. Consistent with previous studies, the most frequent side effects were dissociative symptoms, including derealization, depersonalization, and cardiovascular changes, and increased blood pressure and heart rate, which occurred equally in both groups. There were no serious adverse events in either study group.

The investigators note that most of the previous research examining antidepressant effects of ketamine has used the IV racemic type. The current findings are particularly important for situations in which ketamine or intranasal esketamine, which was recently approved by the US Food and Drug Administration, are unavailable, Quarantini said.

"What our study adds to what has been previously published is that the only way to really analyze if two drugs are equivalent is to compare them in a head-to-head trial; and that was what we did," he said.

"Our findings bring a greater basis for practitioners from locations where intravenous esketamine is more easily obtainable than ketamine to use it as an affordable option for treating depressive patients," Quarantini added.

"Since this [lack of availability] is the scenario here in Brazil, and probably in many other countries, all patients from these locations will benefit from this finding," he said. 

While further evaluating the study results to determine which clinical characteristics were predictive of remission of depressive symptoms, the researchers assessed several key factors. The median duration of disease progression was 12 months, median number of depressive episodes was five, and median number of therapeutic treatment failures was three.

The investigators also looked at the number of suicide attempts and degree of dissociative behavior.

Of these factors, the number of therapeutic failures was the only significant predictor of symptom remission, with an odds ratio of 1.46 for each prior therapeutic failure (95% CI, 1.08 - 1.99).

"To date, we have not found [other] studies with similar data," Quarantini noted.

"Identifying remission predictors may contribute to selecting more suitable candidates for the intervention and result in more individualized and effective patient management," the investigators write.

Consistent Findings

Commenting on the findings for Medscape Medical News, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University School of Medicine, New Haven, Connecticut, noted that key study limitations include the small sample size and lack of a placebo group.

Nevertheless, "I think it is fair to say that it is unlikely that the treatments are markedly different in their effects on depression over 24 hours," he said.

Sanacora, who is also director of the Yale Depression Research Program, was not involved with the current research.

The findings are "consistent with what we can extrapolate from other clinical trials examining racemic ketamine and esketamine separately," he said.

Sanacora noted that because esketamine has been previously shown to be a more potent anesthetic than arketamine, the other component of racemic ketamine, it is "the primary form of ketamine used as an anesthetic agent in several regions of the world with the idea that it may be more selective for the desired anesthetic effect."

Even with its limitations, the study does offer some notable yet preliminary insights, he added.

"It is interesting to see varying degrees of numerical differences between the two treatments at different time points," Sanacora said. In addition, "there may be some differing effects between the two treatments over time, but we really do not have enough data to say much of anything [about that] with confidence at this point."

The study was supported by the Programa de Pesquisa para o SUS through Fundação de Amparo à Pesquisa do Estado da Bahia. Quarantini has reported receiving consulting fees from Allergan, Abbott, Janssen Pharmaceuticals, and Lundbeck, and research fees from Janssen Pharmaceuticals. The other study authors' disclosures are listed in the published article. Sanacora has reported consulting and/or conducting research for Allergan, Alkermes, AstraZeneca, Avanir, Axsome Therapeutics, Biohaven Pharmaceuticals, Bristol Myers Squibb, Clexio Biosciences, EMA Wellness, Eli Lilly, Epiodyne, Intra-Cellular Therapies, Janssen, Johnson & Johnson, Hoffman La Roche, Merck, Naurex, Navitor, NeuroRx, Novartis, Noven Pharmaceuticals, Otsuka, Perception Neuroscience, Praxis Therapeutics, Sage Pharmaceuticals, Servier Pharmaceuticals, Taisho Pharmaceuticals, Teva, Valeant, VistaGen Therapeutics, and Usona Institute. He also holds shares in BioHaven Pharmaceuticals and is co-inventor on a patent called "Glutamate Agents in the Treatment of Mental Disorders."

Anxiety and Depression Association of America (ADAA) Conference 2020. Abstract 1772.

J Affect Disord. 2020;264:527-534. Abstract

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