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.