Abstract
Research over the last two decades has established ketamine as a safe, effective, fast-acting, and sustained antidepressant that significantly reduces adverse symptoms associated with depression, even in patients who are treatment resistant. Much of this research has evolved within the framework of several independent branches of scientific inquiry: in addition to the study of ketamine is a non-selective NMDAR antagonist with rapid antidepressant effects, it has also been found effective as a psychoplastogen that stimulates synaptogenesis and increases neuroplasticity, as a powerful anti-inflammatory that may improve inflammation-related depressive symptoms, as a substance that induces beneficial high entropy brain states, and as a subjectively impactful psychedelic agent. Each branch of inquiry has generated independent evidence of ketamine's efficacy but has advanced without substantive coordination or communication with other lines of inquiry. Integrative research that considers these branches of research together may lead toward a better understanding of ketamine's effects and improved treatment protocols and clinical outcomes. Such an overview can inform more comprehensive patient care through: (a) informed patient psychoeducation that encompasses all of ketamine's mechanisms of action; (b) calibration of optimal dosage to ensure induction and maintenance of high entropy brain states during each ketamine session utilizing EEG measurement; (c) Improved management of emergence side effects through proper care for set and setting; (d) inclusion of pre-selected appropriate music to enhance the emotional experience; (e) increased monitoring of ketamine effects on cortical activity, inter-hemispheric imbalance, and inflammation-related levels of cytokines to further improvements in ketamine protocols; and (f) appropriate timing of any adjunctive psychotherapy sessions to coincide with peak neurogenesis at 24–48 h post ketamine treatment.
Highlights
AND BACKGROUNDThe World Health Organization [1] has declared depression a global epidemic, confirming that over 300 million people suffer from major depressive disorder (MDD) worldwide, a number is increasing exponentially
One branch of inquiry has focused on ketamine’s antidepressant effects as a bi-hemispherical homeostatic glutamate receptor modulator, both as inhibitor and excitor; another has explored ketamine’s effects on chronic stressinduced inflammation; a third has concentrated on the discovery that ketamine stimulates synaptogenesis and dendritic spine growth inherent in neuronal communication and connectivity; a fourth has considered the neurological impact of the psychedelic state associated with ketamine at subanesthetic dosages; and a 5th focus has been on the phenomenology of the ketamine experience and its subjective impact
The results showed that chronic unpredictable mild stress (CUMS) exposed rodents exhibited depression-like behaviors and up-regulated the hippocampal levels of IL-1β, IL-6, TNFα, IDO, and the kynurenine/tryptophan ratio, which were attenuated by a subanesthetic dose of ketamine
Summary
The World Health Organization [1] has declared depression a global epidemic, confirming that over 300 million people suffer from major depressive disorder (MDD) worldwide, a number is increasing exponentially. One branch of inquiry has focused on ketamine’s antidepressant effects as a bi-hemispherical homeostatic glutamate receptor modulator, both as inhibitor and excitor; another has explored ketamine’s effects on chronic stressinduced inflammation; a third has concentrated on the discovery that ketamine stimulates synaptogenesis and dendritic spine growth inherent in neuronal communication and connectivity; a fourth has considered the neurological impact of the psychedelic state associated with ketamine at subanesthetic dosages; and a 5th focus has been on the phenomenology of the ketamine experience and its subjective impact. Integrating the data on ketamine’s five primary characteristic actions—N-methyl-D-aspartate receptor (NMDAR) modulation, neuroplastogenic effects, anti-inflammatory effects, entropic brain state modulation, and psychedelic induction of peak or mystical experiences—may improve treatment protocols and clinical outcomes by guiding educational preparation of patients, optimization strategies for ketamine dosing and dose regulation, informing management of dissociative emergence effects, monitoring impacts on brain activity, and predicting favorable timing for adjunct psychosocial interventions
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