Understanding the physiological changes induced by ketamine in mood disorders, while reducing its side effects, is likely to contribute to a more comprehensive understanding of the physiology underlying mood disorders, as well as to the development of faster-acting and more efficacious antidepressant treatments. An extensive review of the literature on ketamine and the pathophysiology of depression indicates that ketamine's antidepressant efficacy has classically been attributed to noncompetitive antagonism of the n-methyl-d-aspartate receptor (NMDAR) on the neuronal postsynaptic membrane, thereby reducing excessive Ca²⁺ influx through the NMDAR channel. However, recent evidence suggests that ketamine's antidepressant efficacy is mediated not by synaptic NMDAR antagonism but rather by its direct effects on mitochondrial function, arising from its amphiphilic structure. It is proposed that astrocyte mitochondria represent the primary target of ketamine, with the broader effects induced by ketamine occurring downstream of the optimization of astrocyte mitochondrial function and, consequently, astrocyte function. Developmental stress and trauma are proposed to differentially prime specific regions of the central nervous system, rendering them more susceptible to subsequent stressors through the epigenetic regulation of astrocytes. This process increases astrocyte reactivity and dysregulates astrocyte mitochondrial function in response to subsequent stressors, while also increasing blood-brain barrier permeability within these regions. At stress-vulnerable sites, ketamine may upregulate adenosine, humanin, and melatonin, thereby restoring astrocyte function and attenuating inflammatory activity within the local astrocytic microenvironment, including microglia, neurons, and oligodendrocytes. Ketamine's modulation of mitochondrial function is proposed to be mediated via NMDARs located on the inner mitochondrial membrane, leading to alterations in mitochondrial ionic regulation that enhance astrocyte mitochondrial resilience to stress, possibly through a preconditioning mechanism. Ketamine-induced increases in melatonin and humanin are proposed to suppress microglial activation, promote white matter remyelination, and restore neuronal activity, as well as patterned intercellular and interregional communication. This hypothesis-driven overview evaluates ketamine's capacity to restore astrocyte mitochondrial function and thereby counteract the consequences of developmental stress and trauma that underlie vulnerability to subsequent stress-induced depression.
