The Neuroplasticity Hypothesis of Major Depressive Disorder: The Prospective Use of -Like Drugs as Roma Kankaria Virginia Commonwealth University

Introduction Results Conclusions Major depressive disorder (MDD), one of the most common While the novel neuroplasticity hypothesis of MDD focuses on neuropsychiatric diseases, has been cast into the spotlight as Finding #1 Weakened Excitatory Synaptic Transmission how chronic stress alters synaptic transmission, the theory the number of people diagnosed with the disorder has overlaps with the monoamine hypothesis to explain how Inadequate Current Understanding MDD: The emotional and cognitive symptoms seen in MDD patients are not fully increased. Since the 1960s, the monoamine hypothesis of depression presents itself in the brain. understood. Regarding the monoamine hypothesis of MDD, the relationship between monoamine levels and depression is MDD, which states that low levels of monoamine unclear. There is debate regarding the cogency of the hypothesis; while increased monoamine levels can reverse depressive neurotransmitters result in depressive symptoms, has been the While ketamine induces rapid AD-like effects via an NMDAR- symptoms, depression is not likely caused solely by a decrease in monoamine expression. foundation for research in neuropsychology. However, studies mediated mechanism that is not fully understood, many reveal that traditional, biogenic-amine-based antidepressants Neuroplasticity Hypothesis of MDD: Chronic stress damages synaptic strength in areas of the brain involved with reward ketamine-like drugs are more clinically-viable ADs that act via (ADs), like selective reuptake inhibitors (SSRIs), fail behavior, like the hippocampus and the prefrontal cortex. Pre-synaptic and post-synaptic genes that affect cytoskeletal AMPAR-mediated mechanisms. to treat the majority of MDD patients and have long latency rearrangement and glutamate receptor subtypes are dysregulated in the hippocampus of depressed individuals, indicating that periods. Research has noted that the new neuroplasticity stress impairs neuronal communication. Clinical trials with MDD patients and postmortem brain hypothesis, which states that depression is a result of Long-Term Changes in MDD Patients: Long-term changes seen in MDD patients can be attributed to the downregulation analyses of MDD patients should be used to understand if weakened excitatory synaptic transmission, offers a novel of critical genes in regions like the hippocampus. While alterations of serotonin levels play a role in causing anhedonia, acute dual-drug treatments with ketamine-like drugs and mechanism by which ketamine-like drugs, which lack the changes in synaptic excitability also influence the corticomesolimbic reward pathway and, thus, alter hedonic behavior in amine-based ADs could provide rapid and robust symptom abuse liability and psychoactive effects of ketamine, are able MDD patients. relief for treatment-resistant MDD patients. to induce rapid and robust AD-like effects. 17,300,000 50 Finding #2 Ketamine-Like Drugs as AMPAR Potentiators Further Studies The number of adults in the The number of years the Ketamine: Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, induces AD-like effects within 24 hours of Before dual-drug AD treatments are approved for clinical use, United States affected by serotonin hypothesis of acute administration. Ketamine either inhibits NMDARs on gamma-aminobutyric-acid-ergic (GABAergic) inhibitory further research must be conducted on understanding: MDD every year MDD has been relied upon neurons or blocks neurotransmitter-mediated NMDAR activation, thus promoting alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptor (AMPAR) expression. Ketamine has a high abuse liability and psychoactive side effects, 50% 24 which hinder its clinical viability. The percentage of MDD The number of hours it Ketamine-Like Drugs: Ketamine-like drugs—including L-655,708, MRK-016, and (2R,6R)-hydroxynorketamine (HNK)— Treatment effects in human Neuronal mechanism of patients who fail to respond takes many ketamine-like act in a similar manner as ketamine in order to induce rapid AD-like effects but lack harmful side effects. Brain-slice MDD patients treatment to traditional ADs drugs to demonstrate AD- analyses confirm that chronic stress at temporoammonic (TA)-CA1 synapses supresses AMPAR-mediated signaling but does like effects not directly affect NMDAR-mediated signaling. Ketamine-like compounds like (2R,6R)-HNK act like AMPAR potentiators, inducing AD-like effects via an NMDAR-independent mechanism to reverse stress-induced changes in hedonic behavior and synaptic strength. Acute dual-drug dosages Latency period and efficacy needed for rapid AD effects period of treatment Objectives Finding #3 AMPAR Potentiators and Biogenic-Amine-Based ADs: Synergism This study had two main objectives: 1. To understand the long-term substantiality of the AMPAR Potentiators Biogenic-Amine-Based ADs References Duric, V., Banasr, M. Stockmeier, C. A., Simen, A. A., Newton, S. S., Overholser, J. C., … Duman, R. S. (2012). 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