Ketamine and Esketamine Therapy in Affective Disorders: A Comprehensive Review of Mechanisms, Clinical Evidence, Safety, and Future Directions
Kshirsagar Pankaj*, Misal Shivdarshan, Dr. Giri Ashok
Zenodo (CERN European Organization for Nuclear Research) February 28, 2026 DOI: 10.5281/zenodo.18817380 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Randomized Peer reviewed |
|---|---|
| Population | Patients with MDD, bipolar depression, TRD |
| Interventions | Ketamine Esketamine |
| Topics | Depression Ketamine Esketamine |
| Keywords | Suicidal ideation Monoaminergic Dissociative Antidepressant Population Clinical trial Adverse effect Intensive care medicine Sedation Randomized controlled trial |
| Key findings | Ketamine and esketamine provide rapid antidepressant effects for treatment-resistant depression, offering an alternative to standard monoaminergic treatments, but long-term safety and maintenance strategies require further study. |
Abstract
Major Depressive Disorder (MDD) and Bipolar Depression represent significant global health burdens because about one-third of patients who receive standard monoaminergic antidepressant treatment fail to achieve remission. The population with Treatment-Resistant Depression (TRD) needs assistance because they deal with dangerous suicide risks and struggle with their daily activities. The review delivers an extensive assessment of ketamine and esketamine as glutamatergic modulators which medical professionals use to treat affective disorders. The study investigates the N-methyl-D-aspartate (NMDA) receptor antagonism mechanism together with clinical efficacy results from essential randomized controlled trials (RCTs) and drug distribution information and safety issues which include dissociation and cystitis and actual therapeutic use in medical practice. Research shows that intravenous (IV) ketamine at sub-anesthetic levels produces quick antidepressant results which start within hours for patients who do not respond to regular treatments. Esketamine received regulatory approval as an intranasal treatment for TRD and MDD with acute suicidal ideation because of the evidence from the TRANSFORM and SUSTAIN trial programs. The two medications show treatment effectiveness but they need continuous observation because patients experience dissociation and sedation and they have a risk of drug misuse. The conclusion states that Ketamine and esketamine develop a new psychiatric treatment method which replaces current monoamine hypothesis treatments with neuroplasticity-based therapies. The emergency treatment provides immediate results for dangerous medical situations but scientists need to prove its long-term safety track record and create successful methods for ongoing treatment maintenance.