Abstract
Ketamine has been shown to acutely and rapidly ameliorate depression symptoms and suicidality. Given that women suffer from major depression at twice the rate of men, it is important to understand how ketamine works in the female brain. This review explores three themes. First, it examines our current understanding of the etiology of depression in women. Second, it examines preclinical research on ketamine's antidepressant effects at a neurobiological level as well as how ovarian hormones present a unique challenge in interpreting these findings. Lastly, the neuroinflammatory hypothesis of depression is highlighted to help better understand how ovarian hormones might interact with ketamine in the female brain.
Highlights
Reviewed by: Yan Li, Apellis Pharmaceuticals, United States Bernadeta Szewczyk, Maj Institute of Pharmacology, Polish Academy of Sciences (IF PAS), Poland
The etiology of major depressive disorder is complex, and there is no single explanation for its manifestation
Despite the discovery of ketamine’s antidepressant effects being relatively recent, there’s plenty of evidence supporting the various hypotheses concerning its mechanisms of action in the CNS
Summary
There are multiple models suggesting what may cause depression, none of which are mutually exclusive, highlighting the complexity of the underlying etiology. While there is evidence in support this theory, for example monoamine depletion diets [34], there is plenty that contradicts it, i.e., the slow onset and moderate efficacy of antidepressants targeting monoamines [35,36,37,38,39] Another hypothesis, the glutamate hypothesis of depression, posits that MDD is linked to altered glutamate transmission and metabolism in the brain. Brain imaging studies show that individuals suffering from MDD and anxiety-related disorders have smaller hippocampal and prefrontal cortical volumes [44,45,46,47] This theory attributes such atrophy to inflammatory glial cells transitioning to an inflammatory state, causing lowered synaptic clearance, neurotoxicity, and phagocytosis of healthy neurons. These alterations in glutamate metabolism have been intricately associated with depression and treatment resistance [45]
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