Frontiers in pharmacology
January 1, 2025
Agnieszka Zelek-Molik, Ewa Litwa
19 citations
Mood disorders like major depressive disorder and bipolar disorder are leading causes of disability worldwide, characterized by depressed mood, anhedonia, sleep disturbances, appetite changes, fatigue, cognitive impairment, and feelings of worthlessness. A growing number of patients experience treatment resistance, even with long-term therapy, creating an urgent need for rapid-acting and safe antidepressants. This review summarizes trends in novel antidepressant research, focusing on drugs with multi-directional mechanisms and high efficacy for treatment-resistant depression. Animal models of depression remain essential for predicting therapeutic strategies and understanding the physiological effects of new compounds, guiding the development of innovative treatments.
Journal of psychopharmacology (Oxford, England)
July 1, 2024
Mariusz Papp, Piotr Gruca, Ewa Litwa et al.
15 citations
Two compounds that selectively activate serotonin 5-HT1A receptors in a biased manner, NLX-101 and NLX-204, produce rapid antidepressant effects in rats exposed to chronic mild stress, similar to ketamine. When injected directly into the prefrontal cortex, these compounds reversed stress-induced anhedonia, reduced anxiety, and improved working memory deficits. Blocking 5-HT1A receptors in the prefrontal cortex eliminated these benefits, showing that the compounds work specifically through these receptors. The findings suggest that biased agonism at 5-HT1A receptors is a promising strategy for rapid-acting antidepressants that may avoid ketamine's side effects while also addressing cognitive deficits and anxiety.
Behavioural pharmacology
June 1, 2025
Ronan Depoortère, Mariusz Papp, Piotr Gruca et al.
2 citations
Ketamine rapidly reverses depression-like symptoms in rats exposed to chronic mild stress, including loss of pleasure and working memory deficits, when given systemically or directly into the prefrontal cortex. Blocking serotonin 5-HT1A receptors in the prefrontal cortex with WAY-100635 prevents these effects, showing that ketamine's rapid antidepressant and pro-cognitive actions require activation of these receptors. The findings suggest that drugs directly targeting prefrontal cortex 5-HT1A receptors could provide rapid antidepressant effects and improve cognitive deficits without ketamine's side effects or need for clinical supervision.