Ketamine as a prophylactic resilience-enhancing agent

Abstract

Stress exposure is one of the greatest risk factors for psychiatric illnesses, including major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Enhancing stress resilience could potentially protect against the development of stress-induced psychiatric disorders, yet no resilience-enhancing pharmaceuticals have been developed to date. This review serves to consider the existing evidence for a potential pro-resilience effect of ketamine in rodents as well as the preliminary evidence of ketamine as a prophylactic treatment for postpartum depression (PPD) in humans. Several animal studies have demonstrated that ketamine administered 1 week prior to a stressor (e.g., chronic social defeat and learned helplessness) may protect against depressive-like behavior. A similar protective effect has been demonstrated against PTSD-like behavior following Contextual Fear Conditioning (CFC). Recent work has sought to explore if the administration of ketamine prevented the development of postpartum depression (PPD) in humans. Researchers administered ketamine immediately following caesarian-section and found a significantly reduced prevalence of PPD in the ketamine-treated groups compared to the control groups. Utilizing ketamine as a resilience-enhancing treatment may have unique applications, including leading to a deeper understanding of the neurobiological mechanism underlying resilience. Future trials aiming to translate and replicate these findings with humans are warranted.

Sex differences in basal reelin levels in the paraventricular hypothalamus and in response to chronic stress induced by repeated corticosterone in rats

“…The FST has predictive validity for antidepressant efficacy; generally, the time-course that antidepressants work in humans is paralleled by how these same drugs lower rodent immobility in the FST. To give some examples, selective serotonin transporter (SERT) reuptake inhibitors normalize immobility behavior when given chronically (Mukherjee et al, 2015), ketamine does this rapidly and for a period of around 2 weeks (Evers et al, 2022;Fitzgerald et al, 2019). Therefore, our findings show further evidence towards the putative antidepressant actions of reelin which expand also to the post-partum period.…”

The Downstaging Concept in Treatment-Resistant Depression: Spotlight on Ketamine

“…Preliminary evidence in women administered with a single dose of ketamine epidurally shortly after a caesarean cut suggests that ketamine may reduce the risk of developing depressive symptoms after acute stress and postpartum depression. It has been proposed that ketamine could be used as a prophylaxis for soldiers before participation in combat [ 81 ]. The mechanism behind this effect is still unknown, but it likely involves the glutamatergic system, mesolimbic dopamine pathway, PFC, and the hippocampus, and possibly the anti-inflammatory effect of ketamine [ 81 ].…”

“…It has been proposed that ketamine could be used as a prophylaxis for soldiers before participation in combat [ 81 ]. The mechanism behind this effect is still unknown, but it likely involves the glutamatergic system, mesolimbic dopamine pathway, PFC, and the hippocampus, and possibly the anti-inflammatory effect of ketamine [ 81 ].…”

Ketamine’s Amelioration of Fear Extinction in Adolescent Male Mice Is Associated with the Activation of the Hippocampal Akt-mTOR-GluA1 Pathway

“…A similar result was observed in adults [ 25 ], implying that ketamine has the greatest impact during initial exposure to cues previously associated with aversive stimuli. In recent years, preclinical data have also shown that administering ketamine before an acute stressor can attenuate learned fear and prevent the development of PTSD-like behavior in adults [ 51 , 58 , 59 , 60 ], highlighting prophylaxis as one of the potential approaches to ketamine’s clinical application. Here, our findings show that ketamine can reduce fear in adolescents by accelerating FE, suggesting that ketamine can serve as an adjunct to ET for this age cohort.…”