Document Type




Submission Date

May 2021



Major depressive disorder (MDD) affects approximately 17.3 million adults in the United States each year. For more than 50 years, the serotonin hypothesis of MDD, which hypothesizes that a deficiency of monoaminergic neurotransmitters results in depression, has been the foundation for neuropsychological research. However, studies reveal that only an estimated 50% of MDD patients respond to traditional, biogenic-amine-based antidepressants (ADs), like selective serotonin reuptake inhibitors (SSRIs). Research has noted that the neuroplasticity hypothesis, which posits that weakened excitatory synaptic transmission results in depression, offers an alternative mechanism by which ketamine-like drugs lacking the abuse liability and psychoactive effects of ketamine are able to induce AD-like effects. This study focuses on establishing the importance of the neuroplasticity hypothesis of MDD in relation to novel ADs and designing clinical trials that will help determine the most effective and fastest-acting MDD treatments. A compilation of studies involving rodent models of depression, MDD patients, and postmortem hippocampus analyses was examined in order to understand the relationship between long-standing theories and newer hypotheses of how depression manifests in rat and human brains. Research shows that because ketamine-like drugs, including L-655,708 and (2R,6R)-hydroxynorketamine (HNK), modulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) expression to promote neuroplasticity, the novel compounds induce AD-like effects within twenty-four hours and strengthen the brain’s cortico-mesolimbic reward pathway in rodent models of depression. While the monoamine theory and the neuroplasticity theory of MDD focus on different mechanisms by which ADs reverse stress-induced changes in synaptic strength and hedonic behavior, the theories overlap to justify the ability of ketamine-like drugs, which act as AMPAR potentiators, and biogenic-amine-based ADs to augment each other’s activity. More clinical trials must be conducted in order to understand if and how the simultaneous administration of ketamine-like drugs and traditional ADs could result in shorter latency periods and higher efficacies in MDD therapies. Dual-drug treatments that maximize the synergism between long-standing and novel ADs may offer a new therapy method that would alleviate the severe depressive symptoms faced by a large population of treatment-resistant MDD patients


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