Ketamine and Esketamine Therapy in Affective Disorders: A Comprehensive Review of Mechanisms, Clinical Evidence, Safety, and Future Directions
Zenodo (CERN European Organization for Nuclear Research) February 28, 2026 Kshirsagar Pankaj*, Misal Shivdarshan, Dr. Giri Ashok
About one-third of people with major depressive disorder or bipolar depression do not get better with standard antidepressants, a condition called treatment-resistant depression. Ketamine and esketamine, which modulate the glutamate system by blocking NMDA receptors, can produce rapid antidepressant effects within hours when given intravenously at low doses. Esketamine nasal spray is approved for treatment-resistant depression and major depression with suicidal thoughts, based on clinical trials. These drugs offer a new approach focused on neuroplasticity rather than the older monoamine theory, but they require monitoring for side effects such as dissociation, sedation, and potential for misuse. Long-term safety and effective maintenance strategies still need to be established.