Single dose ketamine pharmacokinetic-pharmacodynamic relationships in healthy volunteers

In 2000 the NMDA antagonist ketamine was reported to be an effective fast acting antidepressant in patients with major depressive disorder (MDD), and this has subsequently been confirmed in multiple studies. In addition, single doses of ketamine, at the same dose levels, were shown to have strong effects on anxiety symptoms in patients with post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD). We have recently identified similar effects in patients with refractory Generalized Anxiety Disorder (GAD) and Social Phobia (SP) – (Study 15/STH/86). In all anxiety disorders, there were rapid (within 1h) improvements in anxiety severity that were sustained for 3-7 days, not dissimilar to the responses in patients with MDD. The dose response was also similar, suggesting that the pathophysiology of diverse negative emotional disorders (anxiety, depression) may share a common neurobiology.
We have also been studying aspects of ketamine’s neurobiology, in particular its effects on expression of BDNF, in rats. BDNF is a neurotrophic hormone that appears to have an important general role in the activity of all antidepressants and many anxiolytics.
Another pharmacodynamic endpoint is cognition. One of the side effects of ketamine is changes in cognition, with changes in a range of cognitive domains following lower dose ketamine administration.. These changes were only present until 2 hours post-infusion. In a more recent trial delayed recall was found to be reduced at 40 minutes but a return to baseline was not assessed..
It is possible that ketamine’s effects on cognition are associated with its concentration in blood, and a recent review suggested that levels of 20 ng/mL could affect psychomotor performance.
There are several objectives in this randomised double blind parallel group study:
1. To evaluate the early and later effects of single doses of ketamine on BDNF concentrations in healthy volunteers, and to explore the relationship of BDNF changes with ketamine and metabolite concentrations. This research may help inform biomarker research in patient populations.
2. To evaluate the early and late effects of ketamine on EEG changes
3. To evaluate the magnitude and duration of cognitive changes following a dose of ketamine or placebo in healthy volunteers. Blood testing will also show any associations of cognitive changes with levels of ketamine and its metabolites in the participant’s bloodstream. This research may help to improve the administration method for ketamine in a clinical setting.