A Narrative Review: The Role that Ketamine May Play in the Treatment of Depression and the Underlying Mechanisms of Its Effect

The antidepressant ketamine produces rapid improvements in mood, anhedonia, and suicidal ideation, unlike classic antidepressants such as Selective Serotonin Reuptake Inhibitors. The exact neuropsychopharmacological mechanisms remain unknown, but emerging theories from human and animal studies—including neuroimaging and placebo-controlled crossover randomized trials—focus on neurotransmitter systems, synaptic effects, and changes in functional brain networks. This review concludes that a major mechanism underlying ketamine's antidepressant effects is the reversal of chronic stress pathology present in depression, while also discussing limitations of the evidence.

Study at a glance

Abstract

The novel antidepressant ketamine has been shown to achieve what most classic antidepressants, such as Selective Serotonin Reuptake Inhibitors, have not been able to. A rapid onset of symptomatic improvement across multiple domains; mood, anhedonia, and suicidal ideation. The exact neuropsychopharmacological mechanisms of this unique phenomenon are still unknown, although many theories are emerging from human and animal studies using neuroimaging and placebo-controlled, cross-over randomised control trials. This review discusses current state-of-the-art theories of action, focussing on neurotransmitter systems, effects of ketamine at the synapse, and functional connectivity in the form of brain networks. These theories are discussed in the context of dysfunctionality in depression, concluding that a major mechanism contributing to ketamine’s antidepressant effects is the reversal of chronic stress pathology present in depression. Possible limitations of evidence presented are discussed.