Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants

Abstract

Newer antidepressants are needed for the many individuals with major depressive disorder (MDD) that do not respond adequately to treatment and because of a delay of weeks before the emergence of therapeutic effects. Recent evidence from clinical trials shows that the NMDA antagonist ketamine is a revolutionary novel antidepressant because it acts rapidly and is effective for treatment-resistant patients. A single infusion of ketamine alleviates depressive symptoms in treatment-resistant depressed patients within hours and these effects may be sustained for up to 2 weeks. Although the discovery of ketamine's effects has reshaped drug discovery for antidepressants, the psychotomimetic properties of this compound limit the use of this therapy to the most severely ill patients. In order to develop additional antidepressants like ketamine, adequate preclinical behavioral screening paradigms for fast-acting antidepressants need to be established and used to identify the underlying neural mechanisms. This review examines the preclinical literature attempting to model the antidepressant-like effects of ketamine. Acute administration of ketamine has produced effects in behavioral screens for antidepressants like the forced swim test, novelty suppression of feeding and in rodent models for depression. Protracted behavioral effects of ketamine have been reported to appear after a single treatment that last for days. This temporal pattern is similar to its clinical effects and may serve as a new animal paradigm for rapid antidepressant effects in humans. In addition, protracted changes in molecules mediating synaptic plasticity have been implicated in mediating the antidepressant-like behavioral effects of ketamine. Current preclinical studies are examining compounds with more specific pharmacological effects at glutamate receptors and synapses in order to develop additional rapidly acting antidepressants without the hallucinogenic side effects or abuse potential of ketamine.

Keywords: BDNF; animal models; antidepressants; depression; ketamine.

Figure 1

Following blockade of NMDARs, phosphorylation of Akt activates mTOR complex 1 (mTORC1), which results in increased p70S6K phosphorylation and increased protein translation via inhibition of 4E-BP and release of eIF-4B. Glutamate binds AMPARs, which induces depolarization of the membrane, enabling Ca²⁺ influx through VDCCs. This results in BDNF release from synaptic vesicles. The subsequent binding of TrkB receptors induces ERK and Akt signaling. These pathways all converge to increase synaptic protein translation and receptor trafficking to the cell membrane. Additionally, activation of mTORC2 by S6, and inhibition of GSK-3, induces mTORC1 activation via increased Akt phosphorylation. Furthermore, mTORC2 activation induces protein kinase C (PKC) signaling transduction, which regulates actin and other cytoskeletal proteins.