Novel Treatment Strategies for Major Depressive Disorder: Investigating Ketamine’s Antidepressant Effects and the Role of the c-Jun N-Terminal Kinase Pathway

Abstract

Current first-line treatments for depression, namely monoamine-based drugs such as SSRIs, take weeks to show any clinical effects, and they are only effective in 60-70% of patients. There is therefore an urgent need to develop more rapid and efficacious treatments. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist often used as a dissociative anesthetic, has been found to have rapid (within hours) antidepressant effects, even in historically treatment-resistant patients. Nevertheless, ketamine has its own limitations, such as unwanted side effects and abuse potential. The overarching goal of this thesis was to gain a better understanding of the antidepressant mechanisms of ketamine. Dedication To my family, all of you. Only you know how long this road has really been, and your support has been absolutely paramount. Thank you. v Table of Contents Abstract…………………………………………………………………………………ii Acknowledgements…………………………………………………………………..iii Dedication……………………………………………………………………………...iv Table of Contents…………………………………………………………………......v List of Figures…………………………………………………………………….....viii List of Abbreviations………………………………………………………………..xi Preface………………………………………………………………………………...xiii Chapter 1. General Introduction…………………………………………………1 Chapter 2. Ketamine modulates pro-inflammatory cytokines, but not stressor-induced neurochemical changes……………………………………...27