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Advancing past ketamine: emerging glutamatergic compounds for the treatment of depression.

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Title: Advancing past ketamine: emerging glutamatergic compounds for the treatment of depression.
Authors: Freudenberg, Florian (AUTHOR), Reif-Leonhard, Christine (AUTHOR), Reif, Andreas (AUTHOR)
Source: European Archives of Psychiatry & Clinical Neuroscience. Sep2025, Vol. 275 Issue 6, p1547-1557. 11p.
Subjects: Glutamate receptors, Antidepressants, Glutamic acid, Treatment effectiveness, Ketamine, Neuroplasticity, Methyl aspartate receptors
Abstract: Changes in glutamatergic neuroplasticity has been proposed as one of the core mechanisms underlying the pathophysiology of depression. In consequence components of the glutamatergic synapse have been explored as potential targets for antidepressant treatment. The rapid antidepressant effect of the NMDA receptor antagonist ketamine and subsequent approval of its S-enantiomer (i.e. esketamine), have set the precedent for investigation into other glutamatergic rapid acting antidepressants (RAADs). In this review, we discuss the potential of the different glutamatergic targets for antidepressant treatment. We describe important clinical outcomes of several key molecules targeting components of the glutamatergic synapse and their applicability as RAADs. Specifically, here we focus on substances beyond (es)ketamine, for which meaningful data from clinical trials are available, including arketamine, esmethadone, nitrous oxide and other glutamate receptor modulators. Molecules only successful in preclinical settings and case reports/series are only marginally discussed. With this review, we aim underscore the critical role of glutamatergic modulation in advancing antidepressant therapy, thereby possibly enhancing clinical outcomes but also to reducing the burden of depression through faster therapeutic effects. [ABSTRACT FROM AUTHOR]
Copyright of European Archives of Psychiatry & Clinical Neuroscience is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Advancing past ketamine: emerging glutamatergic compounds for the treatment of depression.
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  Data: <searchLink fieldCode="AR" term="%22Freudenberg%2C+Florian%22">Freudenberg, Florian</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Reif-Leonhard%2C+Christine%22">Reif-Leonhard, Christine</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Reif%2C+Andreas%22">Reif, Andreas</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22European+Archives+of+Psychiatry+%26+Clinical+Neuroscience%22">European Archives of Psychiatry & Clinical Neuroscience</searchLink>. Sep2025, Vol. 275 Issue 6, p1547-1557. 11p.
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  Data: <searchLink fieldCode="DE" term="%22Glutamate+receptors%22">Glutamate receptors</searchLink><br /><searchLink fieldCode="DE" term="%22Antidepressants%22">Antidepressants</searchLink><br /><searchLink fieldCode="DE" term="%22Glutamic+acid%22">Glutamic acid</searchLink><br /><searchLink fieldCode="DE" term="%22Treatment+effectiveness%22">Treatment effectiveness</searchLink><br /><searchLink fieldCode="DE" term="%22Ketamine%22">Ketamine</searchLink><br /><searchLink fieldCode="DE" term="%22Neuroplasticity%22">Neuroplasticity</searchLink><br /><searchLink fieldCode="DE" term="%22Methyl+aspartate+receptors%22">Methyl aspartate receptors</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Changes in glutamatergic neuroplasticity has been proposed as one of the core mechanisms underlying the pathophysiology of depression. In consequence components of the glutamatergic synapse have been explored as potential targets for antidepressant treatment. The rapid antidepressant effect of the NMDA receptor antagonist ketamine and subsequent approval of its S-enantiomer (i.e. esketamine), have set the precedent for investigation into other glutamatergic rapid acting antidepressants (RAADs). In this review, we discuss the potential of the different glutamatergic targets for antidepressant treatment. We describe important clinical outcomes of several key molecules targeting components of the glutamatergic synapse and their applicability as RAADs. Specifically, here we focus on substances beyond (es)ketamine, for which meaningful data from clinical trials are available, including arketamine, esmethadone, nitrous oxide and other glutamate receptor modulators. Molecules only successful in preclinical settings and case reports/series are only marginally discussed. With this review, we aim underscore the critical role of glutamatergic modulation in advancing antidepressant therapy, thereby possibly enhancing clinical outcomes but also to reducing the burden of depression through faster therapeutic effects. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of European Archives of Psychiatry & Clinical Neuroscience is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=188476038
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        Value: 10.1007/s00406-024-01875-z
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        Text: English
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      – SubjectFull: Treatment effectiveness
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      – SubjectFull: Neuroplasticity
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            NameFull: Freudenberg, Florian
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            – D: 01
              M: 09
              Text: Sep2025
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              Y: 2025
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