Research on glutamate release inhibitors, NMDAR antagonism, and glutamate neurotransmission activation has yielded promising results, yet ketamine and other glutamatergic drugs have notable limitations for mainstream use that require further study. Moreover, it is yet to be determined whether synaptic loss and dysconnectivity represent predisposing risk factors, an outcome of stress exposure, or factors that perpetuate psychopathology. The synaptic model posits that CSP is a common pathway across many psychopathologies and that targeting synaptic loss and dysconnectivity may provide mechanistically novel RAADs with the potential to improve the lives of patients with stress-related psychopathology, including suicidality.
Ketamine as a treatment and a tool
Based on this synaptic model of CSP, ketamine’s suspected mechanism of action provides a unique opportunity to:
•Advance our understanding of CSP
•Investigate our ability to reverse neural alterations in CSP and the cognitive, emotional, and behavioral implications of doing so
• Explore ketamine-affected biomarkers of CSP
• Inform novel drug development.
Two ketamine-induced alterations in glutamate neurotransmission may underlie its RAAD effects: (1) an acute burst of glutamate leading to transient prefrontal activation of glutamate neurotransmission and (2) a sustained increase in prefrontal synaptic connectivity. Brief surges of prefrontal glutamate precipitate multiple intracellular processes that ultimately lead to increased synaptic connectivity in the prefrontal cortex approximately 24 hours after a subanesthetic dose of ketamine. Figure 1 shows the suspected pathway of ketamine’s action beginning with postsynaptic activation leading to a glutamate surge and BDNF release, activation of mammalian target of rapamycin signaling, and elevations in synaptic strength and protein synthesis.
Evidence from MRI studies has repeatedly demonstrated reduced prefrontal cortex global brain connectivity in stress-related disorders and suicidality, which suggests that this may be a viable biomarker of CSP.15-17 Human mechanistic studies further support this notion by directly coupling prefrontal cortex global brain connectivity to glutamate neurotransmission, ketamine administration to increased prefrontal cortex global brain connectivity, and this ketamine-induced normalization in connectivity to the RAAD effects and treatment response.14,18 Ketamine has been seen to influence gray matter volume—with increases in the hippocampus and decreases in the nucleus accumbens—at the peak of treatment response.14,15 These ketamine-induced neural alterations in glutamate neurotransmission, global brain connectivity, and gray matter volume provide the opportunity to examine putative biomarkers underlying CSP and RAAD treatment response.
PLEASE NOTE THAT THE POST-TEST IS AVAILABLE ONLINE ONLY ON THE 20TH OF THE MONTH OF ACTIVITY ISSUE AND FOR 18 MONTHS AFTER.
Dr Averill is Clinical Research Psychologist, Clinical Neuroscience Division, Veterans Affairs National Center for PTSD, West Haven, CT; Associate Research Scientist, Department of Psychiatry, Yale School of Medicine, New Haven, CT; and Clinical Director, Emerge Research Program, Department of Psychiatry, Yale School of Medicine. Mr Averill is Neuroimaging & Technology Manager, Emerge Research Program, Clinical Neuroscience Division, Veterans Affairs National Center for PTSD, West Haven, CT and Department of Psychiatry, Yale University School of Medicine. Dr Abdallah is Assistant Professor of Psychiatry, Yale University School of Medicine, and Director of Neuroimaging, Clinical Neuroscience Division, Veterans Affairs National Center for PTSD.
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