Ketamine as an Antidepressant: Mechanisms, Pharmacokinetics, and Its Role in Stress-Related Depression Models

Abstract

Background: Depression is a prevalent mental health disorder characterized by persistent sadness, hopelessness, and a diminished ability to experience pleasure. It significantly impacts mental and physical well-being, altering thought processes and behavior. Individuals with depression often struggle with daily activities, including work, sleep, appetite, and overall quality of life. Animal models of chronic stress provide an experimental ground for investigating various neurobehavioral manipulations associated with depression because stress is one of the most important risk factors for the onset of this disease in humans. Prolonged exposure to a stressful environment during the development of a rodent model frequently leads to behavioral despair, withdrawal from social interactions, and anhedonia- symptoms associated with depression. Traditional antidepressants, despite their widespread use, are limited by delayed therapeutic onset and suboptimal efficacy in many patients. In contrast, ketamine—a fast-acting N-methyl-D-aspartate (NMDA) receptor antagonist—has emerged as a promising alternative. This review aims to provide detailed information on the antidepressant mechanisms of ketamine, emphasizing its impact on depression-related neurobiology, particularly DA dysfunction. It also examines ketamine’s effects on depression-relevant endophenotypes, such as anhedonia and behavioral despair, as well as its activity within the ventral tegmental area (VTA) in rodent models of chronic stress. Conclusion: Ketamine, a fast-acting N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as an innovative treatment for depression, particularly in cases where conventional therapies have failed. Its ability to provide rapid and sustained antidepressant effects often within hours compared to the weeks required for traditional antidepressants has revolutionized the field