Date of Submission
Open Access Senior Thesis
Bachelor of Arts
© 2022 Tristan Reece
Major Depressive Disorder (MDD) is a highly debilitating and common psychiatric disorder that affects over 250 million people globally; it is among the most financially and emotionally burdensome illnesses in the world. Currently approved antidepressants are suboptimal in their efficacy and latency of therapeutic action. In contrast, single administrations of sub-anesthetic ketamine have been shown to rapidly alleviate depressive symptoms within hours, even in treatment-resistant patients. Ketamine is believed to exert these effects by increasing glutamatemediated neurotransmission and promoting rapid neurotrophic factor release, restoring the integrity of neural circuits that are compromised in depression. However, uncertainty surrounding its specific antidepressant mechanism of action has stalled distribution of this promising drug. Here, a chronology of antidepressant treatment advances that preceded the ketamine discovery is detailed, and current hypotheses for ketamine’s antidepressant mechanism are critically reviewed to identify the limits of our understanding. Then, a study addressing a poorly characterized aspect of this mechanism is proposed. The study aims to assess whether isolated ketamine or its active antidepressant metabolite, (2R,6R)-hydroxynorketamine, differ in their ability to ameliorate stress-induced depressive phenotypes within the hippocampus of mice, compared to when they are present in combination. This study will provide insight for ongoing drug discovery efforts. An improved understanding of how ketamine exerts its effects within the brain will help foster future therapeutic innovation, which may lighten the ever-increasing burden of MDD on society.
Reece, Tristan, "Putative Mechanisms Underlying the Antidepressant Actions of Ketamine: A Review and Study Proposal" (2022). CMC Senior Theses. 3047.