Ketamine and Esketamine Therapy in Affective Disorders: A Comprehensive Review of Mechanisms, Clinical Evidence, Safety, and Future Directions

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.

Study at a glance

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.