European archives of psychiatry and clinical neuroscience
August 29, 2024
Florian Freudenberg, Christine Reif-Leonhard, Andreas Reif
10 citations
Changes in glutamate-related brain plasticity may underlie depression, leading researchers to explore components of the glutamate synapse as targets for faster-acting antidepressants. The NMDA receptor blocker ketamine and its S-enantiomer esketamine already show rapid antidepressant effects. This review examines other glutamatergic rapid-acting antidepressants beyond (es)ketamine that have meaningful clinical trial data, including arketamine, esmethadone, nitrous oxide, and other glutamate receptor modulators. Substances successful only in preclinical studies or case reports are discussed marginally. The authors aim to highlight glutamatergic modulation's critical role in advancing antidepressant therapy, potentially improving clinical outcomes and reducing depression's burden through faster therapeutic effects.
The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry
January 1, 2025
Christine Reif-Leonhard, Shannon N Millard, Dorsa Ferdowssian et al.
3 citations
Repeated intravenous esketamine infusions improved emotion recognition for all emotions except sadness, where accuracy decreased, particularly for low-intensity expressions. Misclassifications of other emotions as sad also decreased, indicating a reduced response bias towards sadness. This shift emerged after the first infusion and consolidated over time. Participants showed significant reductions in feelings of sadness and irritability, and cognitive functioning improved. Among those receiving at least five infusions, 66.7% showed significant improvement. The findings suggest that esketamine's antidepressant effects may involve changes in emotion processing and cognition, with acute mood-lifting effects distinguishable from longer-lasting responses that consolidate after repeated administration.
Pharmacological research
October 1, 2025
Florian Freudenberg, Christine Reif-Leonhard, Gerard R Dawson et al.
Treatment-resistant depression (TRD) affects about 30% of patients with major depressive disorder. While antidepressant development has long focused on monoamine targets, research over the past 35 years has increasingly explored glutamatergic mechanisms. This review discusses developments in glutamatergic drug discovery, emphasizing convergent mechanisms between NMDA and AMPA receptor signaling. Beyond established rapid-acting antidepressants like (es)ketamine and dextromethorphan/bupropion, novel directions include esmethadone, nitrous oxide, and NMDA receptor positive allosteric modulators (rapastinel, zelquistinel, apimostinel), as well as AMPA receptor PAMs (osavampator, tulrampator). The convergent mechanism involves increased AMPA receptor activation, triggering BDNF release and mTOR signaling, promoting synaptic strengthening. Glutamatergic agents represent a transformative path for TRD treatment.