Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_205_библиотеки_им_акад_М_И_Перельмана

The first line of investigation that provided a direct link to the development and approval of esketamine as an antidepressant treatment was a series of studies from Phil Skolnick’s laboratory at the National Institutes of Health (Pilc et al. 2013). These studies found evidence of NMDA receptor abnormalities associated with stress­induced rodent models of mood disorders and identified the NMDA receptor as a pharmacological target for antidepressant drug development in the early 1990s. Other work at the time demonstrated that tricyclic antidepressants—in addition to their effects on monoamine neurotransmission—also modified NMDA receptor bind­ing and function, suggesting that the receptor may be involved in the downstream mechanisms of even the classic antidepressants (Reynolds and Miller 1988). In paral lel, there was an increasing awareness of corticolimbic circuitry emerging at the time, and how it related to depressive symptoms. Given that these are largely glutamater gic and GABAergic circuits, it was reasoned that drugs targeting these systems may produce more direct antidepressant effects, not requiring the secondary changes in neurophysiology necessary for the monoaminergic drugs to produce their antide­pressant effects (Krystal et al. 2019). This work provided the foundational evidence for the seminal proof-of-concept study by Berman et al. (2000) demonstrating the an tidepressant potential of ketamine, a well-characterized NMDA receptor antagonist. Remarkably, the findings showed that a single infusion of ketamine produced a rapid onset of antidepressant effects capable of lasting for days after a single administration in a small group of eight patients in a randomized crossover study design. However, interest in developing ketamine as a novel, rapidly acting antidepressant therapy only gained sustained momentum nearly 6 years later following the replication and confirmation efforts by Zarate et al. (2006) at the National Institute of Mental Health. This early work not only spurred interest in ketamine and ketamine-like compounds but also can be credited with more broadly reigniting interest in antidepressant drug development that had waned through the end of the twentieth century.