In search of the mechanisms of ketamine’s antidepressant effects: How robust is the evidence behind the mTor activation hypothesis

Susanna Popp,Therese M Jay,Daniel Deaver,Thomas A Lanz,Per Svenningsson,Berthold Behl,Jaya Julie Joshi,Dorian Caudal,Jacob I Cunningham,Esther Schenker,Michael Spedding,Anton Bespalov

doi:10.12688/f1000research.8236.1

Susanna Popp, Therese M Jay + Show 10 more

Open Access

https://doi.org/10.12688/f1000research.8236.1

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Abstract

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.

Highlights

Ketamine and search for novel antidepressants Intravenous ketamine has been shown to induce a rapid and longlasting antidepressant effect in treatment-resistant patients (Zarate et al, 2006a) and the results have been replicated by several groups (Aan Het Rot et al, 2012)
Ketamine is usually described in the literature as an antagonist acting at N-methyl-d-aspartate (NMDA) subtype of glutamate receptors, and pilot clinical data indicated that its antidepressant effects may be shared at least to some extent by other drugs from this class (e.g. CP 101,606; Preskorn et al, 2008)
Seminal discovery: Ketamine-induced activation of mTOR pathway Li et al (2010) presented a set of data indicating that, in rats, antidepressant-like action of ketamine may be mediated by the activation of mTOR-dependent intracellular cascades

Summary

Introduction

Background: Ketamine and search for novel antidepressants Intravenous ketamine has been shown to induce a rapid and longlasting antidepressant effect in treatment-resistant patients (Zarate et al, 2006a) and the results have been replicated by several groups (Aan Het Rot et al, 2012). Other non-competitive NMDA receptor antagonists appear to lack ketamine’s efficacy at least at the doses free from psychotomimetic effects (memantine: Zarate et al, 2006b; AZD-6765: Sanacora et al, 2014). These controversial findings have called for a deeper understanding of specific biological mechanisms of ketamine’s action. In the study by Li et al (2010), acute injection of ketamine activated the mTOR pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Assuming that something similar can occur in humans, these data may explain why acute infusion of ketamine produces such long-lasting effects in patients with major depression

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