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
Source: OpenAlex
Summary
Ketamine and esketamine offer rapid relief for patients with Treatment-Resistant Depression (TRD), showing effects within hours. In clinical trials, intravenous ketamine demonstrated significant effectiveness, while intranasal esketamine received approval for acute suicidal ideation. Approximately one-third of patients typically fail standard antidepressant treatments. Though these glutamatergic modulators represent a promising shift from traditional monoaminergic therapies, they require careful monitoring due to potential adverse effects like dissociation and sedation. Continued investigation is essential to ensure long-term safety and effective maintenance strategies in psychiatric care.
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.