A randomized pilot study of the prophylactic effect of ketamine on laboratory-induced stress in healthy adults

Sara Costi; Audrey Evers; Manish K Jha; Matthew Klein; Jessica R Overbey; Ki A Goosens; JoColl Burgess; Kelvin Alvarez; Adriana Feder; Dennis S Charney; James W Murrough

doi:10.1016/j.ynstr.2022.100505

A randomized pilot study of the prophylactic effect of ketamine on laboratory-induced stress in healthy adults

Neurobiol Stress. 2022 Nov 29:22:100505. doi: 10.1016/j.ynstr.2022.100505. eCollection 2023 Jan.

Authors

Sara Costi^{1

2

3}, Audrey Evers¹, Manish K Jha¹, Matthew Klein¹, Jessica R Overbey⁴, Ki A Goosens⁵, JoColl Burgess⁵, Kelvin Alvarez¹, Adriana Feder¹, Dennis S Charney^{1

6

7}, James W Murrough^{1

6}

Affiliations

¹ Depression and Anxiety Center, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Psychopharmacology and Emotion Research Laboratory, Department of Psychiatry, University of Oxford, Oxford, UK.
³ Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
⁴ Department of Population Health Science and Policy, Center for Biostatistics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷ Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA.

Abstract

Background: Stress exposure is a key risk factor for the development of major depressive disorder and posttraumatic stress disorder. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced disorders. The administration of ketamine one week prior to an acute stressor prevents the development of stress-induced depressive-like behavior in rodents. This study aimed to test if the prophylactic effect of ketamine against stress also applies to humans.

Methods: We conducted a double-blind, placebo-controlled study wherein 24 healthy subjects (n = 11 males) were randomized to receive either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) intravenously one week prior to an acute stress [Trier Social Stress Test (TSST)]. The primary endpoint was the anxious-composed subscale of the Profile of Mood States Bipolar Scale (POMS-Bi) administered immediately after the TSST. Salivary and plasma cortisol and salivary alpha amylase were also measured at 15-min intervals for 60 min following the stressor, as proxies of hypothalamic pituitary adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axis activity, respectively.

Results: Compared to the midazolam group (n = 12), the ketamine group (n = 12) showed a moderate to large (Cohen's d = 0.7) reduction in levels of anxiety immediately following stress, although this was not significant (p = 0.06). There was no effect of group on change in salivary cortisol or salivary alpha amylase following stress. We conducted a secondary analysis excluding one participant who did not show an expected correlation between plasma and salivary cortisol (n = 23, ketamine n = 11). In this subgroup, we observed a significant reduction in the level of salivary alpha amylase in the ketamine group compared to midazolam (Cohen's d = 0.7, p = 0.03). No formal adjustment for multiple testing was made as this is a pilot study and all secondary analyses are considered hypothesis-generating.

Conclusions: Ketamine was associated with a numeric reduction in TSST-induced anxiety, equivalent to a medium-to-large effect size. However, this did not reach statistical significance . In a subset of subjects, ketamine appeared to blunt SAM reactivity following an acute stressor. Future studies with larger sample size are required to further investigate the pro-resilient effect of ketamine.