Ketamine and Fluoxetine use in Chronic Unpredictable Stress-Driven Depression

Abstract

Background: Chronic unpredictable mild stress (CUMS) is a widely used experimental model to simulate human depression, characterized by persistent mood disturbances and impaired neurobiological function. Despite the widespread use of conventional antidepressants like fluoxetine, a selective serotonin reuptake inhibitor (SSRI), a significant proportion of patients experience inadequate responses, highlighting the urgent need for novel therapeutic approaches. Ketamine, a rapid-acting N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as a promising antidepressant with distinct mechanisms and rapid efficacy. This review explores the potential roles of ketamine and fluoxetine in addressing depression induced by CUMS. We provide an in-depth analysis of the molecular mechanisms underlying the antidepressant effects of Ketamine and Fluoxetine. Fluoxetine exerts its antidepressant effects by enhancing serotonergic neurotransmission, modulating neuroplasticity, and promoting hippocampal neurogenesis over prolonged treatment periods. Meanwhile, ketamine exerts its effects through glutamatergic pathways, enhancing synaptogenesis, restoring synaptic connectivity, and rapidly reversing stress-induced structural deficits. Evidence suggests that ketamine may provide rapid relief of depressive symptoms, offering a critical bridge to fluoxetine’s delayed therapeutic onset. Furthermore, ketamine’s modulation of glutamate signaling may enhance fluoxetine’s neuroadaptive effects, providing a unique synergistic approach to counteract the multifaceted neurobiological disruptions in depression. We also address potential limitations and adverse effects, including the risk of dependency with ketamine and the tolerability concerns with long-term fluoxetine use. Additionally, we explore emerging evidence on the optimal timing, dosage, and sequence of administration to maximize therapeutic outcomes. In conclusion, the review underscores the need for further research into potential roles of ketamine and fluoxetine, as well as their individual contributions to manage CUMS-induced depression. The complementary pharmacological profiles of these agents suggest promising avenues for personalized treatment strategies, offering hope for individuals with treatment-resistant depression and enhancing our understanding of depression pathophysiology. In Conclusion ketamine is a promising agent in treating CUS-driven depression, providing hope for patients with severe, stress-related depressive symptoms. However, its use requires careful consideration of safety, monitoring, and long-term implications. Fluoxetine remains a cornerstone treatment for CUS-driven depression due to its ability to modulate serotonin levels, promote neuroplasticity, and reverse stress-induced neurochemical changes. However, its delayed onset and side effect profile highlight the need for careful patient selection and management. In cases of severe, rapid-onset stress-driven depression, it may be supplemented or preceded by faster-acting interventions like ketamine.