In search of the mechanisms of ketamine's antidepressant effects: How robust is the evidence behind the mTor activation hypothesis [version 1; peer review: 1 approved, 1 approved with reservations]

• Published in: F1000 research Vol. 5; p. 634
• Main Authors: Popp, Susanna, Behl, Berthold, Joshi, Jaya Julie, Lanz, Thomas A, Spedding, Michael, Schenker, Esther, Jay, Therese M, Svenningsson, Per, Caudal, Dorian, Cunningham, Jacob I, Deaver, Daniel, Bespalov, Anton
• Format: Journal Article
• Language: English
• Published: 2016
• Subjects: Cell Signaling; Data Sharing; Neuropharmacology & Psychopharmacology; Pharmacokinetics & Drug Delivery; mTOR; data robustness; depression; ketamine; data sharing
• ISSN: 2046-1402; 2046-1402
• DOI: 10.12688/f1000research.8236.1

Extensive evidence on rapid and long-lasting antidepressant effects of intravenous ketamine motivated efforts to identify underlying mechanisms that would enable development of novel drugs with similar efficacy, but improved safety and pharmacokinetic profiles. It has been suggested that the antidepressant-like action of ketamine may be mediated by the activation of mTOR-dependent intracellular cascades. Therefore, without any coordination or pre-existing agreement, research labs at AbbVie, Servier, Pfizer and Alkermes started independent experiments aiming to reproduce and extend published evidence. More than a dozen experiments conducted by these four independent teams failed to detect robust effects of ketamine on markers reported to be affected in the original study by Li et al. (2010). Thus, detection of the effects of ketamine on mTOR seem to require special conditions that are difficult to identify and establish, at least in some labs. Present results emphasize the importance of publishing detailed methods either within the paper or as supplementary material. This information is essential for follow-up studies that any significant research is likely to trigger. Further, our efforts to identify individual labs that tried to establish ketamine's effects on mTOR highlight the need for a peer-to-peer mechanism of information exchange such as the one being developed by the ECNP Preclinical Data Forum.