Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction

Abstract

Monoamine-based treatments for depression have evolved greatly over the past several years, but shortcomings such as suboptimal efficacy, treatment lag, and residual cognitive dysfunction are still significant. Preclinical and clinical studies using compounds directly targeting glutamatergic neurotransmission present new opportunities for antidepressant treatment, with ketamine having a surprisingly rapid and sustained antidepressant effect that is presumably mediated through glutamate-dependent mechanisms. While direct modulation of glutamate transmission for antidepressant and cognition-enhancing actions may be hampered by nonspecific effects, indirect modulation through the serotonin (5-HT) system may be a viable alternative approach. Based on localization and function, 5-HT can modulate glutamate neurotransmission at least through the 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 receptors, which presents a rational pharmacological opportunity for modulating glutamatergic transmission without the direct use of glutamatergic compounds. Combining one or more of these glutamate-modulating 5-HT targets with 5-HT transporter inhibition may offer new therapeutic opportunities. The multimodal compounds vortioxetine and vilazodone are examples of this approach with diverse mechanisms, and their different clinical effects will provide valuable insights into serotonergic modulation of glutamate transmission for the potential treatment of depression and associated cognitive dysfunction.

Role of calcium, glutamate and NMDA in major depression and therapeutic application

“…Based on localization and function, 5-HT can modulate glutamate neurotransmission at least through the 5-HT1A, 5-HT1B, 5-HT3 and 5-HT7 receptors, which present a rational pharmacological opportunity for modulating glutamatergic transmission without the direct use of glutamatergic compounds (Pehrson and Sanchez, 2014). 5-HT1B receptor agonism increases hippocampal excitatory field potentials through a CaM kinase-dependent pathway (Cai et al, 2013).…”

Cognition in major depressive disorder

“…inhibition) [45]. Moreover, ketamine's effects on measures of neural structures subserving cognitive functions provide a plausible mechanism for pro-cognitive effects of short-term exposure to ketamine [46].…”

Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): enhancing serotonin release by combining serotonin (5HT) transporter inhibition with actions at 5HT receptors (5HT1A, 5HT1B, 5HT1D, 5HT7 receptors)

“…Agents that can change more than one neurotransmitter's release in more than one site (ie, multiple modes of action at multiple nodes within brain networks) at least theoretically have the possibility of changing multiple symptoms linked to multiple circuits. 2,11,12 Thus, it is useful to understand the net effect of the multiple, simultaneous actions of vortioxetine on neurotransmitter release in order to gain insight into its pharmacologic mechanism of action.…”