Intravenous arketamine for treatment-resistant depression: open-label pilot study

This open-label study (n=7) study investigated the antidepressant efficacy of (R-)ketamine (35mg/70kg), which has been implicated by animal studies to be more potent and longer-lasting compared to (S-)ketamine. Results demonstrate (R-)ketamine’s ability to produce a fast and robust antidepressant effect in patients with depression, with potentially greater and longer-lasting effects, greater response rate, and a lower remission rate than effects reported for (S-)ketamine, although this study had a small sample size and lacked placebo-control.

Abstract

Introduction: We aimed to analyze the efcacy and safety of arketamine, the R(−)-enantiomer of ketamine, for treatment-resistant depression (TRD) in humans.

Methods: Open-label pilot trial, seven subjects with TRD received a single intravenous infusion of arketamine (0.5 mg/kg); primary outcome was change in Montgomery–Åsberg Depression Rating Scale (MADRS) 24 h after.

Results: Mean MADRS dropped from 30.7 before infusion to 10.4 after one day, a mean diference of 20.3 points [CI 95% 13.6–27.0; p<0.001]; dissociation was nearly absent.

Discussion: Arketamine might produce fast-onset and sustained antidepressant efects in humans with favorable safety profle, like previously reported with animals; further controlled-trials are needed.”

Authors: Gustavo C. Leal, Igor D. Bandeira, Fernanda S. Correia-Melo, Manuela Telles, Rodrigo P. Mello, Flavia Vieira, Cassio S. Lima, Ana Paula Jesus-Nunes, Lívia N. F. Guerreiro-Costa, Roberta F. Marback, Ana Teresa Caliman-Fontes, Breno L. S. Marques, Marília L. O. Bezerra, Alberto L. Dias-Neto, Samantha S. Silva, Aline S. Sampaio, Gerard Sanacora, Gustavo Turecki, Colleen Loo, Acioly L. T. Lacerda & Lucas C. Quarantini

Summary

Seven subjects with treatment-resistant depression received a single intravenous infusion of arketamine. The mean Montgomery – sberg Depression Rating Scale dropped from 30.7 before infusion to 10.4 after one day.

Introduction

Ketamine and its S(+)-enantiomer, esketamine, can be used to treat depression, even in patients with treatment resistant depression. However, the potential for abuse, psychotomimetic and cardiovascular side-effects, and the relatively short-lived antidepressant effect limit their use.

Findings from animal studies suggest that arketamine, the other enantiomer of ketamine, might have a longer lasting and more potent antidepressant effect than ketamine and esketamine, and without psychotomimetic effects.

Methods

The present study consisted in a pilot trial with an open label design, with subjects aged 18 – 65, with a DSM-5 diagnosis of MDD and failure to respond to at least two adequate antidepressant trials in the current episode.

All subjects received a single intravenous infusion of arketamine (0.5 mg/kg) delivered over 40 min. The study drug was produced using a three-step process.

Subjects were assessed using MADRS, CADSS and heart rate, blood pressure and peripheral blood oxygen saturation during and after the infusion. The primary outcome was the change in MADRS scores from baseline to 1 day after the infusion.

The study was conducted at the Professor Edgard Santos University Hospital from the Federal University of Bahia, in Salvador, Brazil, and was approved by the local Institutional Review Board.

Results

Seven subjects were enrolled, six from outpatient settings and one from the local Psychiatric ward. Mean MADRS scores decreased from 30.7 to 10.4 after 1 day, and decreased by 19.7 points at 60 min, 24 points at 120 and 240 min, and 16.7 points at 7 days.

During the infusion, the mean blood pressure and heart rate remained stable.

The most reported side effect was blurred vision, followed by dizziness, but both were mild and transient.

Discussion

This is the first study to evaluate the antidepressant action of arketamine in humans. The results demonstrate that arketamine produces a fast and robust antidepressant effect in TRD subjects, and that the magnitude of the improvement on the MADRS appeared to be potentially even greater at 24 h than previously reported with racemic ketamine and esketamine. Other studies reported higher blood pressure changes than in our trial, and greater dissociative symptoms than in our trial, but all participants described a feeling of serenity and inner peace post-infusion.

Arketamine exerts its possible antidepressant effect through several mechanisms, but the exact mechanisms remain unclear.

Arketamine would have a longer and more robust effect than ketamine or esketamine, but it would also have a lower incidence of psychotomimetic effects, possibly due to its lower potential to produce dopamine release and reduction of parvalbumin-positive neurons when compared to esketamine.

The main limitations of the study were its open-label nature and small sample size, and the fact that all participants were females.

Conclusion

Arketamine might produce fast-onset and sustained antidepressant effects in TRD patients with a favorable safety profile.

This work was supported by the Programa de Pesquisa para o SUS (PPSUS/BA research grant number 003/2017) and by CAPES.

Compliance with ethical standards

Dr. Quarantini and Dr. Lacerda have received grants and personal fees from several companies.

Dr. Sanacora has received research funding from many companies, including AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Hoffman La-Roche, Merck, Naurex, and Servier, as well as consulting fees from many companies. Yale University has put multiple measures in place to mitigate this conflict of interest.

Study details

Topics studied
Depression

Study characteristics
Open-Label

Participants
7

PDF of Intravenous arketamine for treatment-resistant depression: open-label pilot study