Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders?

Abstract

Large 'real world' studies demonstrating the limited effectiveness and slow onset of clinical response associated with our existing antidepressant medications has highlighted the need for the development of new therapeutic strategies for major depression and other mood disorders. Yet, despite intense research efforts, the field has had little success in developing antidepressant treatments with fundamentally novel mechanisms of action over the past six decades, leaving the field wary and skeptical about any new developments. However, a series of relatively small proof-of-concept studies conducted over the last 15 years has gradually gained great interest by providing strong evidence that a unique, rapid onset of sustained, but still temporally limited, antidepressant effects can be achieved with a single administration of ketamine. We are now left with several questions regarding the true clinical meaningfulness of the findings and the mechanisms underlying the antidepressant action. In this Circumspectives piece, Dr Sanacora and Dr Schatzberg share their opinions on these issues and discuss paths to move the field forward.

A Multifaceted GABAAReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

“…Although a drug may have been shelved for good reasons, new insights into the molecular basis for its clinical efficacy can open new avenues of drug development, as exemplified by the current interest in ketamine as a lead for novel antidepressants (Sanacora and Schatzberg, 2015). Moreover, these explorations can shed light on previous observations for the drug and its target and could potentially reinvent the drug as a useful pharmacologic tool.…”

The Rapidly Acting Antidepressant Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Rapidly Engage Dopaminergic Mood Circuits

“…With subsequent verification in multiple clinical studies, and extension to other NMDA receptor antagonists (cf. Zarate et al, 2006;Abdallah et al, 2015), research into the mechanisms of action of antidepressant effects has been markedly energized (Sanacora and Schatzberg, 2015). Data generated over the past several years have identified key biologic targets underlying the antidepressant-related actions of ketamine.…”

Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains

“…Although this agent is still a nonselective NMDA receptor antagonist, AZD6765 shows 'low trapping' in electrophysiology studies and appears to be well tolerated in humans (Sanacora et al, 2014;Zarate et al, 2013). Unfortunately, the antidepressant efficacy of this agent is now uncertain given that the beneficial effects seen in early clinical testing were not observed in a larger clinical trial (Sanacora and Schatzberg, 2015). A second approach is the development of subtype-selective NMDA receptor antagonists with attention focused on the NR2B subtype.…”