Florian Freudenberg

2 papers in the library · 10 citations · publishing 2024-2025

Papers

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

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.

DOI: 10.1007/s00406-024-01875-z Full text Major depressive disorder Ampa Nmda Rapid acting antidepressant +7

All roads lead to glutamate: NMDA and AMPA receptors as targets for rapid-acting antidepressants.

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.

DOI: 10.1016/j.phrs.2025.107918 Full text Ketamine Major depressive disorder Ampa Nmda +3