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A randomized pilot study of the prophylactic effect of ketamine on laboratory-induced stress in healthy adults
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 acut...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9813787/ https://www.ncbi.nlm.nih.gov/pubmed/36620306 http://dx.doi.org/10.1016/j.ynstr.2022.100505 |
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author | Costi, Sara Evers, Audrey Jha, Manish K. Klein, Matthew Overbey, Jessica R. Goosens, Ki A. Burgess, JoColl Alvarez, Kelvin Feder, Adriana Charney, Dennis S. Murrough, James W. |
author_facet | Costi, Sara Evers, Audrey Jha, Manish K. Klein, Matthew Overbey, Jessica R. Goosens, Ki A. Burgess, JoColl Alvarez, Kelvin Feder, Adriana Charney, Dennis S. Murrough, James W. |
author_sort | Costi, Sara |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9813787 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-98137872023-01-06 A randomized pilot study of the prophylactic effect of ketamine on laboratory-induced stress in healthy adults Costi, Sara Evers, Audrey Jha, Manish K. Klein, Matthew Overbey, Jessica R. Goosens, Ki A. Burgess, JoColl Alvarez, Kelvin Feder, Adriana Charney, Dennis S. Murrough, James W. Neurobiol Stress Original Research Article 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. Elsevier 2022-11-29 /pmc/articles/PMC9813787/ /pubmed/36620306 http://dx.doi.org/10.1016/j.ynstr.2022.100505 Text en © 2022 Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Research Article Costi, Sara Evers, Audrey Jha, Manish K. Klein, Matthew Overbey, Jessica R. Goosens, Ki A. Burgess, JoColl Alvarez, Kelvin Feder, Adriana Charney, Dennis S. Murrough, James W. A randomized pilot study of the prophylactic effect of ketamine on laboratory-induced stress in healthy adults |
title | A randomized pilot study of the prophylactic effect of ketamine on laboratory-induced stress in healthy adults |
title_full | A randomized pilot study of the prophylactic effect of ketamine on laboratory-induced stress in healthy adults |
title_fullStr | A randomized pilot study of the prophylactic effect of ketamine on laboratory-induced stress in healthy adults |
title_full_unstemmed | A randomized pilot study of the prophylactic effect of ketamine on laboratory-induced stress in healthy adults |
title_short | A randomized pilot study of the prophylactic effect of ketamine on laboratory-induced stress in healthy adults |
title_sort | randomized pilot study of the prophylactic effect of ketamine on laboratory-induced stress in healthy adults |
topic | Original Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9813787/ https://www.ncbi.nlm.nih.gov/pubmed/36620306 http://dx.doi.org/10.1016/j.ynstr.2022.100505 |
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