Time of day influences stress hormone response to ketamine

Abstract

Over 50% of depressed patients show hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Conventional therapy takes weeks to months to improve symptoms. Ketamine has rapid onset antidepressant effects. Yet its action on HPA axis activity is poorly understood. Here, we measured the corticosterone (CORT) response to ketamine administered at different times of day in the Wistar-Kyoto (WKY) rat. In male rats, blood was collected every 10 min for 28 h using an automated blood sampling system. Ketamine (5/10/25 mg Á kg) was infused through a subcutaneous cannula at two time points-during the active and inactive period. CORT levels in blood were measured in response to ketamine using a radioimmunoassay. WKY rats displayed robust circadian secretion of corticosterone and was not overly different to Sprague Dawley rats. Ketamine (all doses) significantly increased CORT response at both infusion times. However, a dose dependent effect and marked increase over baseline was observed when ketamine was administered during the inactive phase. Ketamine has a robust and rapid effect on HPA axis function.The timing of ketamine injection may prove crucial for glucocorticoid-mediated action in depression.

Repurposing Ketamine in the Therapy of Depression and Depression-Related Disorders: Recent Advances and Future Potential

“…Consequently, altered CORT concentrations after stress may serve as a potential predictive measure for susceptibility to depression in clinical settings [214]. Moreover, emerging data propose that the temporal administration of ketamine might influence HPA axis activity, given the classic observation that the circadian release of glucocorticoids aligns with diurnal rhythms [215]. Interestingly, there is heightened HPA axis activity in response to ketamine administration during inactivity [215].…”