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.
| Original language | English |
|---|---|
| Pages (from-to) | 121-133 |
| Number of pages | 13 |
| Journal | CNS Spectrums |
| Volume | 19 |
| Issue number | 2 |
| DOIs | |
| State | Published - Apr 2014 |
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Keywords
- N-methyl-D-aspartate (NMDA)
- glutamate
- metabotropic glutamate receptors (mGluRs)
- selective serotonin reuptake inhibitor (SSRI)
- serotonin (5-HT)
- serotonin transporter (SERT)
- vilazodone
- vortioxetine
- α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)
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Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction. / Pehrson, Alan L.; Sanchez, Connie.
In: CNS Spectrums, Vol. 19, No. 2, 04.2014, p. 121-133.Research output: Contribution to journal › Article
TY - JOUR
T1 - Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction
AU - Pehrson, Alan L.
AU - Sanchez, Connie
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
KW - N-methyl-D-aspartate (NMDA)
KW - glutamate
KW - metabotropic glutamate receptors (mGluRs)
KW - selective serotonin reuptake inhibitor (SSRI)
KW - serotonin (5-HT)
KW - serotonin transporter (SERT)
KW - vilazodone
KW - vortioxetine
KW - α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)
UR - http://www.scopus.com/inward/record.url?scp=84901720404&partnerID=8YFLogxK
U2 - 10.1017/S1092852913000540
DO - 10.1017/S1092852913000540
M3 - Article
C2 - 23903233
AN - SCOPUS:84901720404
VL - 19
SP - 121
EP - 133
JO - CNS Spectrums
JF - CNS Spectrums
SN - 1092-8529
IS - 2
ER -