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Background: Racemic ketamine is a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), with the latter regarded as the main isomer for antidepressant effects. However, preclinical data and one open-label human trial suggest arketamine might exert a more potent and longer-lasting antidepressant effect with fewer side effects. We aimed to explore the feasibility of a randomized controlled trial of arketamine for treatment-resistant depression (TRD) and to assess its efficacy and safety compared to placebo., Methods: This is a, randomized, double-blind, crossover, pilot trial (n = 10). All participants received saline and arketamine (0.5 mg/kg) with a one-week interval. Treatment effects were analyzed with a linear mixed effects (LME) model., Results: Our analysis suggested the presence of a carryover effect, so the main efficacy analysis was limited to the first week, which demonstrated a main effect of time (p = 0.038) but not for treatment (p = 0.40) or their interaction (p = 0.95). This indicates that depression improved over time, but without significant difference between arketamine and placebo. Analyzing the two weeks together, findings were the same. Dissociation and other adverse events were minimal., Limitations: This was a pilot study with a small sample and underpowered., Conclusions: Arketamine was not superior to placebo for TRD but demonstrated to be extremely safe. Our findings reinforce the importance of continuing studies with this drug, with better powered clinical trials, perhaps considering a parallel design with higher or flexible doses and repeated administrations., Competing Interests: Conflict of interest Dr. Lacerda reports grants and personal fees from Janssen Pharmaceutical, Daiichi Sankyo, Cristalia Produtos Químicos e Farmacêuticos, Libbs, Pfizer, Myralis Farma, Aché Laboratórios, Hypera Pharma, Sanofi-Aventis, Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, and Forum Pharmaceuticals. Dr. Sanacora, in the last 12 months, has provided consulting services to Ancora, Aptinyx, Axsome Therapeutics, Biohaven Pharmaceuticals, Bristol-Myers Squibb, Clexio Biosciences, Denovo Biopharma, EMA Wellness, Engrail, Gilgamesh, Freedom Biosciences, Intra-Cellular Therapies, Janssen, miCure Therapeutics, Merck, Navitor Pharmaceuticals, Neurocrine, Novartis, Noven Pharmaceuticals, Perception Neuroscience, Praxis, Sage Pharmaceuticals, Seelos Pharmaceuticals, and XW Labs. He has received funds for contracted research from Janssen Pharmaceuticals, Merck, and Usona Institute. He holds equity in Biohaven Pharmaceuticals and has received royalties paid from patent licenses with Biohaven Pharmaceuticals. His employer, Yale University, has a financial relationship with Janssen Pharmaceuticals and may receive financial benefits from this relationship. Other authors have no conflicts of interest to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Anhedonia is a symptom associated with poorer outcomes in depression treatment, including resistance to treatment, higher functional impact and suicidality. Few drugs are known to adequately treat anhedonia in both unipolar and bipolar depression. The NMDA antagonist ketamine has been demonstrated to be effective in rapidly ameliorating anhedonia in depressive episodes. The main aim of present study is to evaluate the anti-anhedonic effect of esketamine, the S-enantiomer of ketamine recently approved for treatment-resistant depression, in unipolar and bipolar depression., Methods: 70 patients with unipolar or bipolar depression were treated with 6 weekly subcutaneous esketamine infusions (0.5-1mg/kg). Anhedonia was measured through MADRS item 8 before and 24h after each infusion., Results: A significant reduction in anhedonia severity was observed (p<0.0001) after 6 infusions. The effect was statistically significant 24h after the first infusion (p<0.001) in both unipolar and bipolar groups and increased with repeated infusions. Anti-anhedonic effect of esketamine did not differ between groups., Limitations: This is an open-label, real-world study. Lack of blinding and of a placebo arm may limit the interpretation of findings., Conclusion: Although preliminary, present findings suggest that repeated subcutaneous esketamine infusions are effective for the treatment of anhedonia in both unipolar and bipolar depressed patients. These results need to be confirmed through replication in larger double-blinded controlled trials., (Copyright © 2020. Published by Elsevier B.V.)

Background: Ketamine and its enantiomers have recently been highlighted as one of the most effective therapeutic options in refractory depression. However, racemic ketamine and esketamine have not been directly compared. The aim of this study is to assess the efficacy and safety of esketamine compared to ketamine in patients with treatment-resistant depression (TRD)., Methods: This is a randomized, double-blind, active-controlled, bicentre, non-inferiority clinical trial, with two parallel groups. Participants were randomly assigned to a 40-min single intravenous infusion of ketamine 0.5 mg/kg or esketamine 0.25 mg/kg. The primary outcome was the difference in remission rates for depression 24 h following intervention using the Montgomery-Åsberg Depression Rating Scale (MADRS), with a non-inferiority margin of 20%., Results: 63 subjects were included and randomly assigned (29 to receive ketamine and 34 to receive esketamine). At 24 h, 24.1% of participants in the ketamine group and 29.4% of participants in the esketamine group showed remission, with a difference of 5.3% (95% CILB -13.6%), confirming non-inferiority. MADRS scores improved from 33 (SD 9.3) to 16.2 (SD 10.7) in the ketamine group and from 33 (SD 5.3) to 17.5 (SD 12.2) in the esketamine one, with a difference of -5.27% (95% CILB, -13.6). Both groups presented similar mild side effects., Conclusions: Esketamine was non-inferior to ketamine for TRD 24 h following infusion. Both treatments were effective, safe, and well tolerated., Trial Registration: Registered in Japan Primary Registries Network: UMIN000032355., Competing Interests: Declaration of Competing Interest LCQ reports consulting fees from Allergan, Abbot, Janssen Pharmaceutical and Lundbeck and research fees from Janssen Pharmaceutical. ALTL reports grants and personal fees from Janssen Pharmaceutical, personal fees from Daiichi Sankyo, Cristalia Produtos Químicos e Farmacêuticos, Libbs, Pfizer, Myralis Farma, Aché Laboratórios, Hypera Pharmaand Sanofi-Aventis, grants from Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, Forum Pharmaceuticalsand from public programs: CNPq and FAPESP; LMS received personal fees from Daiichi Sankyo Brasil, Lundbeck Brasil, Moksha8 Brasil, Takeda Brasil, Pfizer, Sanofi Aventis, and Torrent Pharma. The other authors report no conflicts of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)