Ketamine, an anesthetic used for 50 years, has recently been studied for chronic pain, addiction, and post-traumatic stress disorder. Its rapid antidepressant effects have sparked research into its mechanisms, though the neurobiological basis remains unclear due to complex dose-dependent molecular actions, active metabolites, and facilitation of synaptic plasticity. This review covers ketamine's diverse uses, focusing on its antidepressant effects at molecular, cellular, and network levels, different doses in antidepressant research, and latest hypotheses about its action.
Both pharmacological and non-pharmacological treatments for depression activate TrkB receptors—a known antidepressant target—by inducing a physiological response linked to sedation. Rapid-acting antidepressants trigger TrkB signaling by evoking a state characterized by electroencephalographic slow-wave activity, behavioral immobility, reduced cerebral glucose utilization, and lowered body temperature. This signaling was not impaired in animals with reduced activity-dependent BDNF release but was diminished by maintaining animals in a warm ambient temperature. Preventing the hypothermic response attenuated the behavioral effects of the rapid-acting antidepressant nitrous oxide. The findings suggest that changes in energy expenditure and thermoregulation are essential, but not sufficient, for antidepressant responses, challenging pharmacology-centric hypotheses and highlighting the role of bioenergetics and thermoregulation.