Novel Targets for Fast Antidepressant Responses: Possible Role of Endogenous Neuromodulators

Abstract

The available medications for the treatment of major depressive disorder have limitations, particularly their limited efficacy, delayed therapeutic effects, and the side effects associated with treatment. These issues highlight the need for better therapeutic agents that provide more efficacious and faster effects for the management of this disorder. Ketamine, an N-methyl-D-aspartate receptor antagonist, is the prototype for novel glutamate-based antidepressants that has been shown to cause a rapid and sustained antidepressant effect even in severe refractory depressive patients. Considering the importance of these findings, several studies have been conducted to elucidate the molecular targets for ketamine's effect. In addition, efforts are under way to characterize ketamine-like drugs. This review focuses particularly on evidence that endogenous glutamatergic neuromodulators may be able to modulate mood and to elicit fast antidepressant responses. Among these molecules, agmatine and creatine stand out as those with more published evidence of similarities with ketamine, but guanosine and ascorbic acid have also provided promising results. The possibility that these neuromodulators and ketamine have common neurobiological mechanisms, mainly the ability to activate mechanistic target of rapamycin and brain-derived neurotrophic factor signaling, and synthesis of synaptic proteins in the prefrontal cortex and/or hippocampus is presented and discussed.

Keywords: agmatine; ascorbic acid; creatine; fast-acting antidepressant; guanosine; ketamine.

Figure 1.

The proposed mechanism of action underlying the fast and sustained antidepressant effects of ketamine. It is postulated that ketamine acts antagonizing NMDAR in GABAergic interneurons (a), thereby decreasing inhibitory action of this system on glutamatergic tonus (b). Thus, glutamatergic neurons release glutamate-containing vesicles in the synaptic cleft, which preferentially activates AMPAR, since NMDAR is antagonized by ketamine (c). Upon activation, AMPAR induces a transient sodium influx that depolarizes the cell and activates VDCC, which induces exocytosis of BDNF-containing vesicles. Released BDNF, in turn, activates TrkB receptors. Upon activation, TrkB stimulates signaling pathways, particularly PI3K/Akt/mTOR-mediated pathway. This signaling pathway culminates in the synthesis of synaptic proteins such as synapsin, PSD-95 (which anchors AMPAR), and AMPAR subunit 1 (GluA1), which are inserted to the cell membrane, contributing to synaptogenesis and rapid antidepressant effect of ketamine (d). 4E-BP: eukaryotic initiation factor 4E-binding protein; Akt: protein kinase B; AMPAR: alpha-amino-3-hydroxy-methyl-5-4-isoxazole propionic acid receptor; BDNF: brain-derived neurotrophic factor; GluA1: AMPA receptor subunit 1; GSK-3β: glycogen synthase kinase 3β; mTOR: mechanistic target of rapamycin; NMDAR: N-methyl-D-aspartate receptor; p70S6K: 70 kDa ribosomal protein S6 kinase; PI3K: phosphatidylinositol 3-kinase; PSD-95: postsynaptic density protein-95 kDa; TrkB: tropomyosin receptor kinase B; VDCC: voltage-dependent calcium channels. Figure designed using images from Servier Medical Art and Mind the Graph.