Neuropharmacology 224 (2023) 109344 Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm Glucocorticoid-based pharmacotherapies preventing PTSD Antonio Florido a, b, Eric Raúl Velasco a, Silvia Monari c, d, Marta Cano e, f, Narcís Cardoner e, f, g, Carmen Sandi c, Raül Andero a, b, f, h, i, Laura Perez-Caballero a, b, * a Institut de Neurociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain b Departament de Psicobiologia i de Metodologia de les Ciències de la Salut, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain c Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédèrale de Lausanne, Lausanne, Switzerland d Department of Psychiatry, Geneva University Hospitals HUG, Geneva, 1225, Switzerland e Institut d’Investigació Biomèdica Sant Pau IIB SANT PAU, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain f Centro de Investigación Biomédica En Red en Salud Mental CIBERSAM, Instituto de Salud Carlos III, Madrid, Spain g Department of Psychiatry and Forensic Medicine, School of Medicine Bellaterra, Universitat Autònoma de Barcelona, Barcelona, Spain h Unitat de Neurociència Traslacional, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Institut de Neurociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain i ICREA, Barcelona, Spain A R T I C L E I N F O A B S T R A C T Keywords: Posttraumatic stress disorder (PTSD) is a highly disabling psychiatric condition that may arise after exposure to PTSD acute and severe trauma. It is a highly prevalent mental disorder worldwide, and the current treatment options Glucocorticoids for these patients remain limited due to low effectiveness. The time window right after traumatic events provides Prevention clinicians with a unique opportunity for preventive interventions against potential deleterious alterations in Hydrocortisone brain function that lead to PTSD. Some studies pointed out that PTSD patients present an abnormal function of Cortisol Corticosterone the hypothalamic-pituitary-adrenal axis that may contribute to a vulnerability toward PTSD. Moreover, gluco­ corticoids have arisen as a promising option for preventing the disorder’s development when administered in the aftermath of trauma. The present work compiles the recent findings of glucocorticoid administration for the prevention of a PTSD phenotype, from human studies to animal models of PTSD. Overall, glucocorticoid-based therapies for preventing PTSD demonstrated moderate evidence in terms of efficacy in both clinical and pre­ clinical studies. Although clinical studies point out that glucocorticoids may not be effective for all patients’ subpopulations, those with adequate traits might greatly benefit from them. Preclinical studies provide precise insight into the mechanisms mediating this preventive effect, showing glucocorticoid-based prevention to reduce long-lasting behavioral and neurobiological abnormalities caused by traumatic stress. However, further research is needed to delineate the precise mechanisms and the extent to which these interventions can translate into lower PTSD rates and morbidity. consequently develop PTSD, thus, suggesting that inter-individual dif­ 1. Introduction ferences can confer vulnerability and resilience toward the effects of severe stressors. The lifetime prevalence of PTSD ranges from 1.3 to Posttraumatic Stress Disorder (PTSD) is a highly prevalent mental 12.2% depending on the social background, country of origin, and disorder that some people develop after experiencing a traumatic event. trauma type, with rates above 18% for war veterans and up to 39% in The PTSD diagnosis requires the presence of one or more clusters of sexually abused women (Dohrenwend et al., 2006; Shalev et al., 2017; symptoms after trauma exposure that persist for at least one month and Kessler et al., 2014; Möller et al., 2014). could comprise: intrusive thoughts, avoidance of trauma reminders, There is a range of approaches available to treat PTSD including both negative alterations in cognition, mood, and arousal, and hyper- pharmacotherapy and psychotherapy. First-line treatments of PTSD are reactivity (American Psychiatric Association, 2013). It is reported that forms of psychotherapy, mainly cognitive–behavioral therapy (CBT) and more than 70% of the worldwide population experience a traumatic exposure therapy, but unfortunately, the ratio of patients that do not event at least once in their lives; yet only a subset of individuals fully respond to these approaches is as high as 50% (Kar, 2011). * Corresponding author. Institut de Neurociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain. E-mail address: laura.perez.caballero@uab.cat (L. Perez-Caballero). https://doi.org/10.1016/j.neuropharm.2022.109344 Received 29 September 2022; Received in revised form 7 November 2022; Accepted 15 November 2022 Available online 17 November 2022 0028-3908/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/). A. Florido et al. Neuropharmacology 224 (2023) 109344 Abbreviations fMRI Functional magnetic resonance imaging GABA Gamma-aminobutyric acid 18F-FDG 18F-fluorodeoxyglucose GR Glucocorticoid receptors ACTH Adrenocorticotropin hormone HPA Hypothalamus-pituitary-adrenal AMT Autobiographical memory retrieval task HRQL Health-related quality of life ASR Amplitude of the startle response ICU Intensive care unit AVP Arginine vasopressin peptide MR Mineralocorticoid receptors BDNF Brain-derived neurotrophic factor NF-κB Nuclear factor-κB BLA Basolateral amygdala PET Positron emission tomography CBT Cognitive–behavioral therapy PPM1F Protein phosphatase 1F CRH Corticotropin-releasing hormone PSD-95 Postsynaptic density-95 CRHR1 CRH type 1 receptors PTSD Posttraumatic stress disorder BOLD Blood oxygenation level-dependent PVN Hypothalamic paraventricular nucleus DEX Dexamethasone SNP Single nucleotide polymorphism EPM Elevated plus maze Currently, the use of antidepressants as therapeutic agents is widely 2. Glucocorticoids dynamics in PTSD spread in clinical settings, although their efficacy is generally smaller compared to the observed in psychotherapy-based interventions (Lee Traumatic experiences typically trigger a stress response involving et al., 2016). Since a substantial proportion of patients present symp­ the fast-acting autonomic nervous system and the slow-acting HPA axis. toms or maintain the PTSD diagnosis after therapy (Steenkamp et al., The final products of the HPA axis, glucocorticoids, are released into the 2015; Stein et al., 2006; Zohar et al., 2002), novel therapeutic strategies bloodstream from the adrenal glands (Herman, 2013). Glucocorticoids should be developed to address this important gap in the prevalence of (i.e., cortisol and corticosterone being the most prominent ones in PTSD. humans and rodents, respectively) promote brain and body functions Epidemiological findings have identified that certain stressors are that facilitate adaptation and recovery when individuals face stressful more likely than others to result in a PTSD diagnosis, such as sexual challenges. Specifically, their life-sustaining functions include the abuse or car accidents (Perkonigg et al., 2000). Thus, the possibility of mobilization of substrates for energy metabolism, the suppression of preventing PTSD development is gaining relevance due to the prompt primary immune and inflammatory responses, and the modulation of identification of risky situations. In this line, prevention strategies are cognitive processes (de Kloet et al., 2005; Sandi, 2011, 2013; Ulrich-Lai classified as primary, secondary, or tertiary (Campion et al., 2020). and Herman, 2009). Primary prevention strategies focus on reducing the risk of exposure to Upon stress, the activation of the HPA axis elicits the release of trauma or decreasing its pathogenicity. Secondary prevention strategies corticotropin-releasing hormone (CRH) from the hypothalamic para­ are used once the traumatic exposure has occurred and regardless of the ventricular nucleus (PVN). CRH reaches the anterior pituitary via the degree of symptoms, but before the onset of a full PTSD diagnosis. hypophysial portal vessels where it binds CRH type 1 receptors Tertiary prevention is focused on PTSD patients, and interventions are (CRHR1), promoting the synthesis of pro-opiomelanocortin, the pre­ given along with treatments to hamper disease progression and cursor of adrenocorticotropin hormone (ACTH). ACTH is released in the disability once the diagnosis has been established (Campion et al., systemic circulation and stimulates the release of cortisol by the adrenal 2020). Therefore, secondary prevention strategies offer the opportunity cortex. In parallel to CRH release, the vasopressin peptide (AVP), whose to delay or avoid the onset of the disease once a traumatic exposure has main role is to maintain the proper volume of water in the extracellular occurred, acting as powerful agents that might hamper the progress of body fluid, is also released. Indeed, when AVP is colocalized with CRH in the consequences of stress exposure. Psychological secondary preven­ the parvocellular neurons of the PVN, AVP amplifies its action on ACTH tion interventions were found to have positive evidence supporting their release, a process that could play an important role in sustaining chronic use, although no universal consensus regarding their effectiveness has stress effects (Ulrich-Lai and Herman, 2009). In addition, vasopressin been established, and their use is not routinely recommended (Bisson acts in the brain via V1, V2 and V3 receptors involved in various aspects et al., 2021; Roberts et al., 2019). Studies that have tested pharmaco­ of social behaviour (Wersinger et al., 2002), as well as in emotional and therapies, including beta-blockers or benzodiazepines, as preventive cognitive processing (Wersinger et al., 2002). interventions for PTSD show conflicting results with little or no con­ Corticosteroids exert their functions by binding to the mineralocor­ trasted full efficacy for the available treatments (Bertolini et al., 2022; ticoid receptors (MR) and glucocorticoid receptors (GR) which act via Sijbrandij et al., 2015). genomic and non-genomic mechanisms (Kloet and Joëls, 2020; Popoli Given the traumatic nature of the disease, alterations in the stress et al., 2011; Reul and de Kloet, 1985). In the brain, MR are mostly response via Hypothalamus-Pituitary-Adrenal (HPA) axis responsive­ expressed in neurons from limbic areas, but GR are found ubiquitously, ness are likely to be at the core of PTSD vulnerability.Thereby the in both glial cells and neurons, with the highest number in the PVN and modulation of glucocorticoid levels in the moment of the traumatic hippocampus. MR are involved in the appraisal of novel situations and experiences could protect against its development. Classical ideas in the adaptation processes during the onset of the stress response, while GR, field point at glucocorticoids as mediators of stress-induced impair­ having a 10-fold lower affinity for corticosterone, play a crucial role in ments. Novel research has arisen proving the efficacy of glucocorticoid the stress response lingering after exposure to an actual stressor. In administration in the aftermath of trauma as a plausible strategy for particular, it facilitates the recovery from stress experiences by mobi­ secondary prevention against PTSD. The present work reviews clinical lizing energy resources and by terminating the stress reaction via and preclinical literature on glucocorticoid administration’s efficacy in negative feedback on multiple nodes of the HPA axis (Kloet and Joëls, the prevention of the deleterious consequences of trauma. 2020; Sandi, 2011, 2013). MR and GR act in a coordinated manner when facing a stressor (de Kloet et al., 2019; de Quervain et al., 2019). MR act rapidly at the onset of stress, initiating the stress response by selecting an adequate coping mechanism through non-genomic mechanisms. Then, 2 A. Florido et al. Neuropharmacology 224 (2023) 109344 upon the termination of stress, MR-GR and GR-GR dimers and GR ER following the trauma accurately predict a major risk of non-remitting monomers promote adaptation to future stressors through genomic ac­ PTSD later on, and this finding was stronger when the subject had a tions that facilitate recovery, rationalisation and contextualisation of the history of childhood trauma (Galatzer-Levy et al., 2017). These results stress response (de Kloet et al., 2019). suggest glucocorticoid-based therapy in the aftermath of trauma might It was first hypothesized that PTSD patients would respond to trauma be relevant for preventing the development of PTSD, in particular in with high cortisol release, given the sustained urinary catecholamine subjects who experienced childhood trauma. levels found in these patients (Kosten et al., 1987; Yehuda, 2002). Another important field of research for the study of PTSD is genetics, However, an early study conducted on Vietnam war veterans reported due to a specific genetic background that might explain, at least low cortisol levels in PTSD subjects compared to other psychiatric pa­ partially, the altered HPA axis responsiveness associated with PSTD tients (Mason et al., 1986). This first report triggered substantial inter­ (Yehuda et al., 2011). In particular, the phistory of PTSD inone parent is est. As commented by the authors, “… this finding of low, stable cortisol linked to an increased risk for the development of PTSD in trauma- levels in PTSD patients is especially noteworthy, first because of the exposed offspring. In a study analyzing the offspring of Holocaust sur­ overt signs of anxiety and depression, which would usually be expected vivors, low cortisol was found in the offspring of PTSD subjects and was to accompany cortisol elevations, and second because of the concomi­ linked to a major vulnerability to developing PTSD in life (Yehuda and tant chronic increase in sympathetic nervous system activity”. Yet, such Bierer, 2007). Recently, a follow-up study, using the same database, observations were not confirmed in later reports (Elzinga et al., 2003; elegantly showed that low glucocorticoid levels in the adult offspring of Maes et al., 1998), indicating substantial variability in the outcome of Holocaust survivors were associated with differentially expressed genes, cortisol measurements across studies. Indeed, there are important dif­ in particular, enriched for glucocorticoid-regulated genes and immune ferences in the cortisol levels observed in PTSD studies. Several factors, pathways (Daskalakis et al., 2020). including the type of samples collected for cortisol measurement and the Several studies on candidate genes point out the presence of single circadian time of sample collection, sex, circadian hormonal fluctua­ nucleotide polymorphisms (SNP) in PTSD patients that are related to GR tions, the presence of comorbidities, and tobacco consumption are function or measures of GR function, directly or via the experience of known to influence HPA activity (Meewisse et al., 2007; Oyola and trauma during childhood (Binder et al., 2008; Mehta et al., 2011; Van Handa, 2017; Rohleder and Kirschbaum, 2006; Van Den Heuvel et al., Zuiden et al., 2012). For example, in a recent meta-analysis of 2019; Yehuda et al., 2005). Of note, early-life trauma exposure may HPA-related genes from both traditional SNP and new gene-level especially contribute to develop a PTSD phenotype in adulthood by methods, a significant relationship between PTSD and NR3C1 (which inducing changes in brain development. Although the literature is less encodes for GR) and FKBP5 (a co-chaperon protein regulating the GR clear when it comes to single trauma exposure during childhood, chil­ sensitivity) at the gene level was reported (Sheerin et al., 2020). dren under chronic abuse develop an HPA axis sensitization that may Moreover, the gene level meta-analysis of CRHR1 was also significant contribute to pathology during adulthood (Pratchett and Yehuda, 2011). when associated with PTSD, but the result was not equally robust as it An important factor that may contribute to the discrepancies in the re­ did not survive multiple testing corrections (Sheerin et al., 2020). ported results is the choice of the appropriate control group across Furthermore, allelic variants of FKBP5 have been linked to biologically studies. While some trials use non-trauma-exposed controls, others distinct PTSD subtypes about GR function (Mehta et al., 2011). Overall, contemplate trauma-exposed controls without PTSD(Klaassens et al., these findings suggest that HPA axis alterations may be critical in 2012; Morris et al., 2012). In addition, the life cycle at the moment of determining PTSD pathophysiology and underscore the view that low trauma seems also to be an important factor affecting cortisol levels. In cortisol levels constitute a pre-existing risk factor to develop PTSD, one meta-analysis of 47 articles, the lowest cortisol levels at awakening probably induced by early-life adversity, instead of a consequence of the were found in patients that were exposed to trauma during childhood trauma. Thus, research on the HPA axis profile before and in the after­ compared to adulthood (Morris et al., 2012). Moreover, this math of a trauma is still ongoing and will eventually shed light on meta-analysis pointed out that the strength and reliability of findings neurobiological mechanisms underpinning the preventive response of examining cortisol levels in PTSD patients are influenced by several glucocorticoids. factors, therefore particular attention should be paid to the study design. In addition, the characterization of specific biobehavioral pheno­ The evaluation of glucocorticoid levels in response to a challenge types and HPA axis parameters among PTSD patients and/or individuals -which reflects HPA reactivity- is biologically relevant. The most at risk following trauma might provide an opportunity for clinical consistent finding among PTSD patients is an important suppression of intervention in this field. One of the main roles of glucocorticoid stress cortisol in response to dexamethasone (DEX), which denotes an hormones is to modulate the mnemonic processing of emotionally enhanced negative feedback inhibition of the HPA axis (Lange et al., arousing experiences (de Quervain et al., 2016; Sandi, 2011, 2013; Sandi 2005; Newport et al., 2004; Yehuda et al., 2002, Yehuda, 2009b). The and Pinelo-Nava, 2007). Years of research have pointed out that glu­ enhanced negative feedback is supposed to be the consequence of a cocorticoids exert divergent effects depending on the specific memory greater GR sensitivity, as suggested by the increased GR responsiveness process (timing) -such as consolidation, retrieval, extinction, and in response to DEX administration (Daskalakis et al., 2013a; Yehuda reconsolidation- as well as their context of occurrence in information et al., 2009). However, other mechanisms, such as a stress-induced processing (de Quervain et al., 2009; Joëls et al., 2006). Specifically, increased CRH release from the amygdala (Makino et al., 1999), or a early work showed that acute administration of corticosteroids enhances reduced ability of the adrenals to produce cortisol (Heim et al., 2000), memory consolidation of emotionally relevant experiences (Sandi et al., might also impair the glucocorticoid negative feedback. 1997; Sandi and Rose, 1994a, 1994b), but impairs memory retrieval of Traditionally, it was assumed that low cortisol levels in association already stored information (de Quervain, 1998). Likewise, impaired with PTSD were a consequence, rather than a cause, of trauma. How­ cognitive function is typically found in conditions associated with ever, data from recent studies suggest that this feature may reflect a pre- elevated glucocorticoids, which might occur when individuals are existing vulnerability trait as a consequence of epigenetic modifications exposed to traumatic or repeated stressful events (McEwen, 2000; Sandi, induced by early-life adversity. One of the first remarkable observations 2004). Interestingly, the intracranial administration of the selective GR in support of the existence of a priori vulnerability captured by cortisol antagonist mifepristone given right before or after the first session of a responsiveness was the finding that individuals displaying low cortisol Morris water maze task disrupts recall in the following session, while the levels in the emergency room (ER), immediately after the traumatic same approach before session 2 does not affect recall, proving a direct event, were the ones eventually developing PTSD (Yehuda et al., 1998). effect on contextual memory consolidation rather than in acquisition or In line with this finding, a recent study using a powerful machine retrieval of memories (Oitzl and de Kloet, 1992). learning analysis showed that decreased levels of cortisol collected at the Specifically, glucocorticoids promote the consolidation of contextual 3 A. Florido et al. Neuropharmacology 224 (2023) 109344 features of fear memories in the dorsal hippocampus (Cordero et al., shorter intensive care unit (ICU) stay, and lower vasopressor 1998, 2002; Cordero and Sandi, 1998) and emotional traits in the (noradrenaline) doses during surgery. Further testing showed that hy­ amygdala and ventral hippocampus through synergistic actions with drocortisone was more effective in patients showing multiple catecholamines (Roozendaal et al., 2004, 2009). Imbalances in neuro­ sub-symptom categories and that prior PTSD memories increased the transmitter levels can result in the “over-consolidation” of traumatic risk for traumatic memories after surgery. In the study with the largest experiences. The persistence of a hyperactive amygdala could explain number of participants from all the reviewed studies (>500 per arm), the exaggerated response of fear response, as well as explain symptoms DEX was given parenterally as a single dose (1 mg/kg) before surgery, of PTSD such as hypervigilance and hyperarousal (Rauch et al., 2000). PTSD, HRQL, and depressive symptoms were evaluated at one variable Moreover, glucocorticoid administration also enhances fear extinction timepoint (18–48 months) (Kok et al., 2016). No differences were found (Galatzer-Levy et al., 2017; Jovanovic et al., 2011; Merz et al., 2017; for PTSD, depressive symptoms, or HRQL. However, subgroup analyses Sawamura et al., 2016; Yang et al., 2006). In particular, DEX adminis­ showed that DEX may improve PTSD and depressive symptoms in tration has been shown to enhance extinction learning and its retention women. of the learned fearful memory in both rodents and humans (Jovanovic Two studies investigated whether hydrocortisone could improve et al., 2011; Sawamura et al., 2016; Yang et al., 2006), along with PTSD outcomes in septic shock patients (Denke et al., 2008; Schelling inducing a transient suppression of the HPA axis. By modulating et al., 2001). Demographic data is not available for one study (Denke different memory processes, glucocorticoids can contribute to reducing et al., 2008), and in the other, the sample consisted mostly of men high fear responses, by both supporting fear extinction and reducing the around 50 years old (Schelling et al., 2001). For both studies, hydro­ retention of aversive memories (Sandi, 2011, 2013; de Quervain et al., cortisone was administered parenterally during ICU stay at variable 2016), or facilitating contextual previously consolidated memory pro­ intervals and doses (0.18 mg/kg/h or 50 mg each 6h) with 6 additional cesses by acting on the hippocampus (Bohus and Lissák, 1968; Cai et al., days of tapering. No differences in PTSD symptom severity were found 2006). Although glucocorticoids have typically shown to have a facili­ (Schelling et al., 2001) or reported (Denke et al., 2008). Nevertheless, tating role in learning, glucocorticoids exert opposing roles on memory lower PTSD rates for the hydrocortisone group (1/9 hydrocortisone, consolidation depending on the timing of stress and context of retrieval 7/11 placebo) were found in one study (Schelling et al., 2001). Hydro­ (Kirschbaum et al., 1996). High cortisol levels right before the acquisi­ cortisone was also related to lower and shorter doses of vasopressor tion of a learning task impair the consolidation of declarative memories therapy (noradrenaline) and better clinical outcomes in the ICU (Kirschbaum et al., 1996); whereas it can be facilitated when stress (Schelling et al., 2001). exposure takes place at the same time and in the same context of the Four studies focused on hydrocortisone interventions shortly after acquisition (Joëls et al., 2006). traumatic injury (Carmi et al., 2022; Delahanty et al., 2013; Shaked One of the theoretical bases supporting the use of glucocorticoids et al., 2021; Zohar et al., 2011a). The study participants were mostly after traumatic stress arises from their capacity to alter memory men and around 35 years old. Amnesic patients, seriously injured or consolidation, impair memory retrieval, enhance extinction memories, needing surgical intervention were discarded. Two studies selected and enhance fear extinction after a context-dependent fear memory specifically patients that had a high risk of dissociation or with promi­ reactivation (de Quervain et al., 2009; Cai et al., 2006). Importantly, nent posttraumatic symptoms (Carmi et al., 2022; Delahanty et al., these effects are highly dependent on the timing of glucocorticoid 2013). Hydrocortisone was administered parenterally in three studies as administration and their convergence with noradrenaline actions in the a single dose (100–140 mg) within 6 h after trauma (Carmi et al., 2022; amygdala and hippocampus (de Quervain et al., 2009). This evidence, Shaked et al., 2021; Zohar et al., 2011a) and orally (20 mg/12 h for 10 accompanied by data suggesting that PTSD patients have disruptions in days plus tapering) starting within 12 h after trauma (Delahanty et al., HPA function, has led to evaluate the efficacy of glucocorticoid 2013). PTSD symptoms were assessed at variable time points after administration at different time windows after the trauma. trauma. In one study, hydrocortisone resulted in a large reduction of PTSD symptom severity at the 2-week and 3-month assessments, while 3. Clinical evidence PTSD rates were not significantly different among groups (3/8 placebo-, 1/9 hydrocortisone-cases). Also, hydrocortisone improved anxiety and 3.1. Prevention of PTSD with glucocorticoids depressive symptoms (Zohar et al., 2011a). However, a follow-up study failed to replicate these findings but found that hydrocortisone was Efforts have been made to test whether glucocorticoid therapy could beneficial for PTSD severity if patients were clustered by trauma time (at be beneficial for PTSD prevention (Table 1). In August 2022, we iden­ night versus at day) (Carmi et al., 2022). In another study, hydrocorti­ tified 9 published studies that used glucocorticoids as preventive ther­ sone reduced overall PTSD symptoms, but this effect was moderated by apy for PTSD, of which 8 used hydrocortisone and 1 DEX. prior mental health treatment, as treatment was most effective in pa­ Hydrocortisone (cortisol) is the naturally occurring glucocorticoid in tients not having any prior mental health care (Delahanty et al., 2013). man, short-acting (8–12h), and usually devoid of mineralocorticoid In the last study, no differences were detected for PTSD symptoms at the activity because of its enzymatic degradation in target tissues. DEX is a 1-month assessment, but subgroup analyses showed that hydrocortisone long-acting (>36h) synthetic corticosteroid with a 50-fold potency than resulted in worse clinical outcomes and greater PTSD symptoms in the hydrocortisone, acting as a GR agonist with no mineralocorticoid ac­ group with low cortisol at admission (9.5 μg/dl cutoff) (Shaked et al., tivity. Cortisol binds to the glucocorticoid-preferring MR in the brain 2021). and heart, which does not bind DEX. Meta-analyses and systematic reviews have shown that hydrocorti­ Two studies with hydrocortisone (Schelling et al., 2004; Weis et al., sone is beneficial for the prevention of PTSD onset and PTSD intensity 2006) and one with DEX (Kok et al., 2016) tested whether PTSD could be when assessing outcomes at the nearest point to 3 months post- prevented in high-risk patients undergoing a planned cardiac surgery intervention or at the study endpoint. However, no evidence for hy­ with cardiopulmonary bypass. Participants were on average around 70 drocortisone benefits was observed if outcomes were assessed specif­ years old and mostly men. For hydrocortisone studies, a placebo or drug ically at 3 months or more than 6 months post-intervention (Amos et al., (100 mg bolus + 10 mg/h) was administered parenterally as an infusion 2014; Astill Wright et al., 2019; Bertolini et al., 2022; Bisson et al., 2021; starting before surgery and tapered over 3 days. Posttraumatic symp­ Kothgassner et al., 2021; Sijbrandij et al., 2015). One meta-analysis that toms and health-related quality of life (HRQL) were assessed at 6 included studies using universal prevention (in all the exposed) and months. In both studies, hydrocortisone was beneficial for decreasing indicated prevention (exposed with symptomatology) found moderate PTSD severity and in one study it also improved quality of life (Weis quality evidence for hydrocortisone efficacy for PTSD intensity (4 et al., 2006). Hydrocortisone was also related to lower IL-6 levels, studies, RR = 0.17, CI (95%) 0.05–0.56) with a number needed to treat 4 A. Florido et al. Table 1 Selected characteristics of preventive studies using glucocorticoids for PTSD. All studies were randomized, two-arms, double-blind and placebo-controlled, except for Schelling et al. (2004) single-blind and compared against standard therapy. BDI= Beck Depression Inventory, bol = bolus, C = control, CAPS= Clinician-Administered PTSD Scale, CES-D = Center for Epidemiological Studies-Depression, d = day, h = hour, ICU = intensive care unit, IV = intravenous, mo = month, n.s. = not specified, NA = noradrenaline, PDS= Posttraumatic Stress Diagnostic Scale, PO = oral, PTSS-10 = Posttraumatic Stress Symptom 10-Question Inventory, QOL = quality of life, SCID-IV= Structured Clinical Interview for the DSM-IV, SD = single dose, SF-36 = Short Form Health Survey 36-item, SRIP= Self Rating Inventory for Posttraumatic stress disorder, TX = treatment, VAS = visual analogue scale, w = week. ID Demographics Drugs Assessments Outcomes First Year Age Gender part per Trauma type Intention Medication Dosage Time points Instruments Outcomes Other outcomes Author (men/ arm (type of patient) (route) of outcome total) (placebo, assessment TX) Schelling 2004 C 69 (64–75), C 20/26, 22, 26 Cardiac surgery Preventive Hydrocortisone bol (100 mg) 6 mo PTSS-10 Lower PTSD symptoms in IL-6 is lower in TX 70 (64–75) TX 15/ + ICU stay (high- before (IV) + 24 h (10 hydrocortisone. Subgroup: hydrocortisone 22 risk) trauma mg/h) + hydrocortisone benefits patients tapering 3 d with multiple symptom categories Weis 2006 C 69 (63–73), C 9/14, 14,14 Cardiac surgery Preventive Hydrocortisone bol (100 mg) 6 mo PTSS-10 Lower PTSD symptoms in Better QOL, shorter TX 68 (63–72) TX 10/ + ICU stay (high- before (IV) + 24 h (10 mod, SF-36 hydrocortisone. PTSD rate 1/14 ICU stay, lower NA 14 risk) trauma mg/h) + hydrocortisone vs 3/14 placebo doses, lower IL-6 in tapering 3 d (p > 0.05) hydrocortisone Kok 2016 C 69.6 C 435/ 564, 561 Cardiac surgery Preventive Dexamethasone SD (1 mg/kg) 18 mo–48 SRIP, BDI, No differences in PTSD No differences in (63.4–76.2), 561, TX + ICU stay (high- before (IV) mo SF-36 symptoms or rates. Subgroup: depressive symptoms. TX 68.4 443/564 risk) trauma women’s prevalence was lower Subgroup: (62.2–75.9) in dexamethasone 4/52 vs hydrocortisone placebo 16/66 women had lower rates of depression Schelling 2001 C 55 (25–75) C 5/6, 11, 9 Septic shock + Preventive Hydrocortisone bol (100 mg) 31 mo SCID-IV, No differences in PTSD Lower NA doses in TX 48 (23–76) TX 3/6 ICU stay (high- during (IV) + 6 d (0.18 (21–49) PTSS-10 mod symptoms. PTSD rates 1/9 hydrocortisone 5 risk) trauma mg/kg) + hydrocortisone vs 7/11 placebo tapering (14–35 d) Denke 2008 n.s. n.s. 9, 9 Septic shock + Preventive Hydrocortisone 5 d (50 mg 12 mo PTSS-10, SF- PTSD symptoms were not ICU stay (high- during (IV) q.6 h) + 6 36 reported. No differences in risk) trauma d tapering PTSD rate Zohar 2011 C 34 (22–62), C 6/8, 8, 9 Traffic accident, Preventive Hydrocortisone SD (100–140 Before, 2 w, CAPS, VAS Lower PTSD symptoms in Lower anxiety and TX 36 (20–62) TX 3/9 work accident after trauma (IV) mg) 1 mo, 3 mo hydrocortisone at 2 w and 3 mo. depression in (excl. seriously PTSD rates 1/9 hydrocortisone hydrocortisone injured) vs 3/8 placebo (p > 0.05) Carmi 2022 C 40.4 (12.6), C 22/45, 45, 51 Traffic accident, Preventive Hydrocortisone SD (100–140 0, 2 w, 1 mo, CAPS. VAS No differences in PTSD No differences TX 38.1 (12.5) TX 24/ work accident, after trauma (IV) mg) 3 mo, 8 mo, symptoms or rates. Subgroup: 51 violence (excl. 13 mo trauma time (at night vs at day); seriously injured) placebo night had higher symptoms than placebo day + hydrocortisone night had lower PTSD prevalence than Neuropharmacology 224 (2023) 109344 hydrocortisone day Delanthy 2013 C 33.8, TX 27.2 C 21/33, 33, 31 Traffic accident, Preventive Hydrocortisone 10 d (40 mg/ 1 mo, 3 mo CAPS, CES-D Lower PTSD symptoms in Better QOL and lower TX 21/ falls (excl. after trauma (PO) d) + 6 self-report, hydrocortisone. Subgroup: depressive symptoms 31 seriously injured, d tapering SF-36 hydrocortisone benefits mostly in hydrocortisone incl. high risk of patients without a psychiatric dissociation) history Shaked 2021 n.s. n.s. 39, 38 Traffic accident Preventive Hydrocortisone SD (100 mg) 1 mo PDS No differences in PTSD after trauma (IV) symptoms. Subgroup: Hydrocortisone low cortisol group had greater PTSD symptoms A. Florido et al. Neuropharmacology 224 (2023) 109344 of 7–13 patients to prevent PTSD in one patient (Amos et al., 2014). physiological responses or PTSD symptoms, but daily doses (600 mg/d) However, studies were found to be at high risk of bias due to differential reduced PTSD symptom intensity and clinical severity (Golier et al., dropouts and small sample sizes. Other meta-analysis found that hy­ 2012; Wood et al., 2015). drocortisone may reduce the chances of experiencing PTSD when used It is especially relevant to overcome the heterogeneity in the re­ as universal prevention (2 studies, RR = 0.23, CI (95%) 0.06–0.96), but ported results on treatment efficacy with glucocorticoid-based drugs. this finding was labeled as unclear evidence due to a high risk of bias This heterogeneity may arise from sociodemographic conditions, trau­ given the imprecise effect estimates and small sample sizes (Bertolini matic stress sources, routes of administration for hydrocortisone, and et al., 2022). Other systematic reviews and meta-analyses have found different dosages employed, which differ among studies. Although that hydrocortisone is better than placebo for preventing PTSD onset limited, the data provided suggests that treatment with hydrocortisone and intensity by combining universal and indicated prevention ap­ might result beneficial to a specific population of PTSD patients that proaches (Astill Wright et al., 2019; Bisson et al., 2021; Sijbrandij et al., present specific conditions, such as the war-related nature of the trauma 2015). In addition, one meta-analysis (Kothgassner et al., 2021) pooled or a greater lifetime severity of PTSD symptoms. Also, the reactivation of studies that used hydrocortisone in a preventive and curative context traumatic memories in a clinically controlled environment lacks strong and found evidence for its efficacy for PTSD symptoms (8 studies, d = contextual features, which may result in an insufficiently recruited 0.96 CI (95%) 0.22 to 1.69) and lower PTSD incidence (5 studies, log RR traumatic memory. The administration of glucocorticoids for an = 0.85, CI (95%) 0.12 to 1.59). However, further analyses showed that incompletely reactivated memory may result in treatment efficacy that the benefits were constrained to studies using hydrocortisone in a pre­ is lost when the patient is transferred to their normal environment. ventive setting and with a parenteral route of administration. Therefore, the recruitment of the contextual features of trauma may Overall, these analyses show the possible effect of hydrocortisone potentiate the effectiveness of glucocorticoids and their proposed administration on the prevention of PTSD after severe stress. However, memory-disrupting properties (al Abed et al., 2020; Huff et al., 2011). the reviewed studies and their conclusions should be weighed against Likewise, it should be further explored how exogenous glucocorticoids their limitations. Most of the available trials have small sample sizes, modulate the contextual processing impairments seen in PTSD patients different hydrocortisone dosages, variable timings for treatment efficacy (Garfinkel et al., 2014). assessment and different scales used for PTSD characterization and severity. Moreover, the samples in the studies are highly heterogeneous 3.2.1. Neuroimaging effects of glucocorticoid administration in terms of age, trauma history, and the nature of the traumatic expe­ In addition to evaluating the therapeutic profile of glucocorticoid rience. Potential sources of bias include high attrition rates and differ­ administration in PTSD patients, considerable efforts have been made to ential dropouts that are more likely in the treatment group. Notably, identify the precise brain areas and networks related to the effect of some studies reported that hydrocortisone was related to better clinical glucocorticoid administration on PTSD patients. To the best of our outcomes, shorter ICU stays, and lower noradrenaline doses, suggesting knowledge, only five studies have evaluated the neuroimaging un­ an alternative explanation for the increased PTSD risk in placebo groups derpinnings of glucocorticoid administration (versus placebo) in pa­ (Schelling et al., 2001; Weis et al., 2006). Further, these studies pointed tients with PTSD and trauma-exposed healthy participants. Thus, a at relevant variables to consider in future research, such as a history of noticeable study explored resting-state brain metabolism in response to psychopathology and trauma, sex as a biological variable, endogenous a parenteral hydrocortisone administration (17.5 mg) using 18F-fluoro­ cortisol levels, and concomitant drug therapy since all of these variables deoxyglucose (18F-FDG) positron emission tomography (PET) in men appear to be modulators of the hydrocortisone treatment effects. with and without combat-related PTSD. Hydrocortisone administration appeared to eliminate group differences in the hemispheric laterality of 3.2. Treatment of PTSD with glucocorticoids the hippocampus and the ventral amygdala. Specifically, hydrocortisone increased the relative metabolic rate in the right hippocampus of the Studies exploring hydrocortisone as a curative intervention in pa­ PTSD group and the left ventral amygdala in the non-PTSD group. In tients with a PTSD diagnosis show mixed results (Table 2). One study addition, hydrocortisone restored the inverse relationship between the administered a single bolus of hydrocortisone (4 mg/kg) after memory anterior cingulate cortex and amygdala in PTSD individuals (Yehuda reactivation in a sample of men with combat-related PTSD and found a et al., 2009). Another study with a similar methodology and a parenteral temporary reduction of PTSD symptoms (1-week post-treatment) that administration of hydrocortisone (17.5 mg) to male combat veterans was not maintained over time (1-month post-treatment) (Surís et al., with and without combat-related PTSD found that hydrocortisone 2010). In other two studies with a crossover design oral hydrocortisone increased the hippocampal metabolic activity in the PTSD group and was administered for 1 month (10–30 mg/d) to patients with PTSD decreased it in the non-PTSD group, especially in the right hippocampus secondary to heterogeneous traumas (Aerni et al., 2004; Ludäscher (Yehuda et al., 2010). et al., 2015). One study with 3 patients showed some positive effects for Moreover, the effects of an oral hydrocortisone administration (10 the hydrocortisone-treated group over the frequency and intensity of mg) on blood oxygenation level-dependent (BOLD) signal during an reexperiencing symptoms and physiological distress (Aerni et al., 2004), autobiographical memory retrieval task (AMT) inside a functional but the one including a larger sample found null results (Ludäscher et al., magnetic resonance imaging (fMRI) scanner in healthy participants and 2015). Two other studies used hydrocortisone to augment exposure patients with PTSD was investigated in women. Whole-brain activity therapy outcomes in men with combat-related PTSD. Participants were patterns during AMT did not differ between conditions or groups given 30 mg of oral hydrocortisone shortly before the exposure therapy (neither in the placebo condition nor after hydrocortisone administra­ session and PTSD outcomes were assessed at variable intervals (Yehuda tion). Notwithstanding, they found that childhood trauma may be et al., 2015; Lehrner et al., 2021). One of the studies found lower PTSD related to brain activity responsiveness to hydrocortisone. In this sense, symptoms in the hydrocortisone group, especially in patients with Childhood Trauma Questionnaire scores were positively associated with greater PTSD lifetime severity (Yehuda et al., 2015). The other study hydrocortisone-induced activation of the anterior medial prefrontal found beneficial effects of exposure therapy over time but no effects for cortex, ventrolateral prefrontal cortex, posterior cingulate cortex, hydrocortisone, although in subgroup analyses patients with angular gyrus, and cerebellum during AMT (Metz et al., 2019b). The post-concussive symptoms and receiving hydrocortisone had lower hy­ same research team also used resting-state fMRI to assess hippocampal perarousal symptoms (Lehrner et al., 2021). Two other small studies and amygdalar functional connectivity. However, these analyses did not explored the efficacy of mifepristone, progesterone, glucocorticoid, and reveal hydrocortisone-induced hippocampal or amygdalar functional androgen receptor antagonist. A single oral dose (1800 mg) before connectivity changes (Metz et al., 2019b). Besides, cerebral perfusion memory reactivation did not result in significant differences in was evaluated in the context of script-driven trauma imagery during an 6 A. Florido et al. Table 2 Selected characteristics of curative studies using glucocorticoids for PTSD. All studies were randomized, two-arms, double-blind and placebo-controlled, except for Ludäscher et al., 2015 and Aerni et al. (2004) with a crossover design. Wood et al. (2015) had 3 arms. BDI= Beck Depression Inventory, C = control, CAPS= Clinician-Administered PTSD Scale, d = day, EMG = electromyography, IES-R = Impact of Event Scale-Revised, IV = intravenous, MINI = Mini-International Neuropsychiatric Interview, mo = month, MR = memory reactivation, n.s. = not specified, NMR = no memory reactivation, PCL= PTSD CheckList, PDS= Posttraumatic Diagnostic Scale, PDS= Posttraumatic Stress Diagnostic Scale, PE= Prolonged exposure therapy, PO = oral, PSS-SR= PTSD Scale-Self Report, QIDS-SR = Quick Inventory of Depressive Symptomatology, SCL-90R = Symptom Checklist 90-Revised, SD = single dose, SD = single dose, TX = treatment, w = week. ID Demographics Drugs Assessments Outcomes First Year Age Gender part per Trauma type (type Intention Medication Dosage Time points of Instruments Outcomes Other outcomes Author (men/ arm of patient) (route) outcome total) (placebo, assessment TX) Suris 2010 n.s. only men 10, 9 Combat-related Curative after Hydrocortisone SD (4 mg/kg) 0, 1 w, 1 mo CAPS, IES-R. No overall differences No differences in military trauma MR (IV) QIDS-SR in PTSD symptoms. At 1 physiological (PTSD) w lower avoidance/ measures (heart rate, numbing in skin conductance hydrocortisone but not response, corrugator, maintained at 1 mo. and frontalis EMG) Ludäscher 2015 30.7 only 15 Childhood sexual Curative Hydrocortisone 7 d (placebo) x3/d intrusions. IES-R. IES-R No differences (19–44) women abuse, sexual and (PO) + 7 d (10 mg) 1/w PTSD intrusions. SCL- physical abuse +7 intensity 90R (PTSD) d (placebo) + 7 d (30 mg) Aerni 2004 40–55 2/3 3 Terrorist attack, Curative Hydrocortisone 1 mo (10 mg/ self > daily, CAPS self- Variable results, lower assault, traumatic during (PO) d) clinical administered. intensity, and injury (PTSD) habitual TX administered > Clinical frequency of monthly. 3 mo interview reexperiencing/ physiological distress 7 symptoms Yehuda 2015 C 44.2 only men 5, 11 Combat-related Curative PE Hydrocortisone 7 times (30 0, post-tx, 6 w CAPS. PSS-SR. Lower PTSD symptoms Responders to (14.5), TX military trauma augmentation (PO) mg) BDI in hydrocortisone hydrocortisone had 54.9 (PTSD >50 CAPS) group. Subgroup: the highest pre- (12.7) Greater improvements treatment in people with greater glucocorticoid lifetime PTSD severity sensitivity that diminished over the course of treatment Lehrner 2021 C 34.6 C 27/30, 30, 30 Combat-related Curative PE Hydrocortisone 8 times (30 0, 1 w and 3 mo CAPS self- No effects of Patients with higher (7.68), TX TX 27/30 military trauma augmentation (PO) mg) administered. hydrocortisone. baseline 36.0 (PTSD >60 CAPS, MINI. PDS. BDI Subgroup: patients with glucocorticoid (8.07) excl. mod-severe current post concussive sensitivity had a TBI) symptoms and greater reduction of hydrocortisone had avoidance symptoms lower hyperarousal with hydrocortisone symptoms Wood 2015 C 40.5 C 13/15, 15, 15, 13 Heterogeneous Curative Mifepristone 1 time (1800 0 and 1 w IES-R. CAPS No differences No differences in Neuropharmacology 224 (2023) 109344 (11.7), TX TX + MR (PTSD) before MR (PO) mg) physiological + MR 44.7 10/15, measures (heart rate, (10.4), TX TX + NR skin conductance + NMR 10/13 response, corrugator 46.8 and frontalis EMG) (14.5) Golier 2012 48.8 only men 4, 4 Combat-related Curative Mifepristone 7 d (600 mg/ 1 mo CAPS. PCL Lower PTSD symptoms (26–63) military trauma (PO) d) in mifepristone. PTSD (PTSD) rate 1/4 mifepristone vs 3/4 placebo A. Florido et al. Neuropharmacology 224 (2023) 109344 arterial spin labeling fMRI acquisition after an oral hydrocortisone modulates important traits of PTSD in rodents. However, rats repeatedly administration (20 mg) in participants exposed to earthquake-related exposed to cat litter present heterogeneous anxiety and avoidance re­ trauma with and without PTSD. Regional blood flow during the sponses. Indeed, rats might be classified as low, moderate, or extreme trauma script presentation did not show any significant effects on con­ responders depending on their scores in the elevated plus maze (EPM) dition, group, or condition by group (de Kloet et al., 2016; Douglas et al., and the amplitude of startle response (ASR) tests. An example of this 2019). type of research is carried out by Cohen et al. (2006), in which they Overall, current research appears to underline the role of the hip­ compared anxiety and fear responses in different rat strains exposed to a pocampus, amygdala, and prefrontal cortex, which are characterized by predator odor with or without prior corticosterone treatment. This study a high density of corticosteroid receptors (de Kloet et al., 2016), in the aims at establishing the role of genetically predetermined corticosterone neurobiological mechanism of action of hydrocortisone in patients with response to stress in the prevalence of PTSD, and then to study the PTSD. However, the use of four different neuroimaging methodologies involvement of corticosterone administration in highly affected rats as (resting-state PET, task-based BOLD fMRI, resting-state BOLD fMRI, and shown by extreme responses in the EPM and ASR tests. Interestingly, task-based ASL fMRI) and small sample sizes do not allow to arrive at administration of corticosterone 1 h before predator odor exposure de­ robust conclusions, and they should be considered only preliminary. creases the prevalence of extreme behavioral responders from 50% to Indeed, one of the possible reasons for the negative findings observed in 8%, showing a preventive role of corticosterone in a highly prevalent three of the published studies (Douglas et al., 2019; Metz et al., 2019a, strain of rats that show posttraumatic stress responses (Cohen et al., 2019b) is the lack of statistical power derived from assessing small 2006). The authors of this study suggest that activation of the HPA axis sample sizes. Moreover, the actions of glucocorticoids are conditional just before traumatic stress might help the HPA axis produce an effective and time-dependent, a fact that should be also considered in further reaction to subsequent stress and thus prevent the development of studies. PTSD-related symptoms. Interestingly, a follow-up study by Cohen et al. In addition, the effects of hydrocortisone may vary as a function of (2008) demonstrates that administering corticosterone right after dose and route of administration. In this sense, single relatively low oral predator scent exposure reduces the anxiogenic consequences of trau­ doses of 10–20 mg may lead to not enough intense effects to display matic stress 31 days after stress exposure (Cohen et al., 2008). These significant neuroimaging findings. Clinical trials have used a 40 mg results suggest that the administration of corticosterone, nearly before therapeutic dosage of hydrocortisone during a course of a few days of or after trauma exposure, confers some type of resilience against the treatment (Yehuda et al., 2010; 2009). Interestingly, the two studies long-term consequences of severe stress. reporting a significant direct impact of hydrocortisone on brain meta­ Another widely used model to induce a PTSD-like phenotype in ro­ bolism used an intravenous injection, which may be an easier route to dents is immobilization stress since it has been shown to trigger several cross the blood-brain barrier compared to oral administration. More­ neurobiological alterations in rodents (Andero et al., 2011; Velasco over, these were the only studies focusing their analyses on men, et al., 2022; Wingo et al., 2018). Using immobilization as a traumatic therefore, a sex-specific effect of hydrocortisone cannot be discarded stress model, the administration of corticosterone at any time from 12 h (Yehuda et al., 2010; 2009). Although current literature arises relevant before stress to 24 h after stress, has been shown to prevent the and interesting questions, further research is warranted to ascertain the anxiety-like behavior induced by immobilization stress (Chakraborty neuroimaging underpinnings of glucocorticoid administration in pa­ et al., 2020; Rao et al., 2012). Even more, the anxiolytic effect of tients with PTSD. post-stress corticosterone is also accompanied by a prevention of the impairment in social interaction, and a significant reduction of circu­ 4. Preventive role of glucocorticoids in animal models of PTSD lating corticosterone 12 h after the treatment (Chakraborty et al., 2020). Further studies in mice prove that a single administration of a high dose As beforementioned, clinical research highlights the role of gluco­ of corticosterone 1 h after acute and severe stress protects mice against corticoid administration in preventing the development of PTSD after the anxiogenic and depressive effects of immobilization. These effects exposure to an acute and intense stressor. Following this line, various are accompanied by the restoration of the protein phosphatase 1F researchers have carried out preclinical studies to delve into the mech­ (PPM1F) expression in the medial prefrontal cortex and the amygdala anisms underlying the preventive role of glucocorticoids in the negative (Wingo et al., 2018). consequences of stress. Corticosterone administration has also been tested in other models of PTSD. For instance, the administration of hydrocortisone 1 h after ex­ 4.1. Preventive corticosterone modulation of behavioral and cognitive ploding a thin copper wire which produces multi-sensorial stress in rats, function prevents the PTSD-like phenotype as measured by enhanced perfor­ mance in an EPM, but not in the ASR (Zuckerman et al., 2017). Similarly, To evaluate the efficacy of glucocorticoid administration in pre­ a 3-day paradigm with restraining unescapable tail-shock stress in­ venting both the behavioral and the neurobiological consequences of creases the ASR, which is mitigated by a corticosterone administration trauma most of the research has employed PTSD-like animal models. To from 30 min before to 30 min after the stress (Jia et al., 2015). Inter­ reproduce some of the critical neurobiological features of PTSD, current estingly, insufficient bedding and nesting materials during the primary models focus on exposing animals to different types of stressors (Das­ stages of development induce social interaction deficits during adoles­ kalakis et al., 2013b). Among them, inescapable foot shocks, exposure to cence, accompanied by lowered circulating corticosterone and ACTH, a predator’s scent (for instance, cat’s or fox’s urine) or single prolonged and increased GR in the medial prefrontal cortex and the dorsal hip­ stress such as immobilization on board are the ones that show better pocampus (Perry et al., 2019). However, the administration of cortico­ apparent validity, since these models can reproduce emotional alter­ sterone 30 min before the social approach test results in effective rescue ations such as high anxiety, depressive-like behaviors or impairment in of the healthy phenotype (Perry et al., 2019), therefore suggesting that fear memory (Richter-Levin et al., 2019). Indeed, all these models have corticosterone administration during adolescence might also palliate also in common an overactivation of the HPA axis and a long-term some of the deleterious effects of early-life stress. impairment of emotional responses that are sensitive to the adminis­ Aberrant fear memories are a key feature of PTSD, and fear neuro­ tration of antidepressants or benzodiazepines palliating the deleterious circuitry is closely related between humans and rodents (Andero et al., effects of stress (Bentefour et al., 2015; Smith et al., 2011). 2013; Mahan and Ressler, 2012). Corticosterone administration affects Accordingly, the possible effect of glucocorticoid administration fear memory in a dose-dependent manner since its administration after protecting against the deleterious effect of trauma has been explored predator stress prevents the increased freezing during the retrieval phase using predator scent models. Exposure to a predator scent model of contextual fear conditioning (Cohen et al., 2008). However, 8 A. Florido et al. Neuropharmacology 224 (2023) 109344 corticosterone does not affect cued-fear retrieval 48 or 96 h after its treatment (Zohar et al., 2011a). Additionally, rats expressing extreme administration, although fear renewal is decreased (Wang et al., 2014). responses after traumatic stress show increased expression of the Notwithstanding, corticosterone administration after cued fear condi­ immunophilin protein FKBP5 and decreased expression of GR and MR in tioning also suppresses fear-potentiated anxiety as measured by the EPM the ventral hippocampus and PVN; while the opposite expression 1-week after the administration (Wang et al., 2014). The data reported pattern is observed in the dorsal hippocampus (Danan et al., 2021). on glucocorticoid treatment after stress highlights a preventive role of Further, this study proves that the AVP, which has been associated with this intervention on enhanced retrieval of contextual, but not cued fear the sensitization of the negative feedback mechanism that regulates the conditioning, suggesting an important role of the hippocampus and HPA axis (Whitaker and Gilpin, 2015), is more expressed in the supra­ contextual learning and memory in the attenuated fear retrieval of optic nucleus of the hypothalamus compared to moderate and low re­ corticosterone-treated animals. Interestingly, the disruption of contex­ sponders and no stress-exposed rodents (Danan et al., 2021). These tual fear memory consolidation is hypothesized to mediate the findings provide a tentative molecular explanation for corticosterone-induced resilience towards subsequent stressors (Cohen hippocampal-HPA axis regulation disturbances in PTSD-vulnerable et al., 2008). Moreover, administration of corticosterone 1 h before animals. exposure to cat litter does not affect learning, extinction, or reversal Further, in rodents, treatment with corticosterone after traumatic learning in the Morris water maze, suggesting that spatial memory re­ stress reverts alterations in the spinogenesis and glutamatergic trans­ mains unaltered after the corticosterone treatment (Cohen et al., 2006). mission that are observed in the amygdala, a brain region crucial in the Furthermore, corticosterone administration after the familiarization regulation of emotional responses after stress. Single 2 h immobilization phase of the object recognition task impairs memory retrieval only at a stress increases spinal density in principal neurons of the basolateral high dose. Interestingly, predator scent stress exposure increases loco­ amygdala (BLA) 10 days after stress, correlating with an increase in motor activity, and this increase was significantly higher in rats that anxiety-like behavior. Corticosterone administration in drinking water receive corticosterone compared with saline-treated animals (Cohen before stress prevents this increase in spinal density, especially in the et al., 2008), pointing to possible motor alterations caused by proximal region of the dendrite (Rao et al., 2012). Furthermore, corti­ glucocorticoids. costerone administration in drinking water 24 h after stress also pre­ Blood samples revealed that reduced secretion of corticosterone in vents the increase in spinal density in primary apical dendrites of BLA basal conditions is predictive of greater anxiety and avoidance re­ principal neurons, accompanied by a lower anxiety-like behavior sponses, correlating with a decreased corticosterone response to (Chakraborty et al., 2020). In line with these results, a metaplasticity following stressors (Danan et al., 2018; Cohen et al., 2006). Interest­ study in vitro showed that one pulse of corticosterone induces a ingly, mild and low responder rats do not present reduced corticosterone long-lasting enhanced glutamatergic transmission in BLA neurons, while pulses in basal conditions nor a decreased HPA axis response toward previous immobilization stress exposure or a single corticosterone pulse stressors (Danan et al., 2018). Furthermore, the administration of prevents this enhanced glutamatergic transmission (Karst et al., 2010). corticosterone in the aftermath of predator odor exposure decreases the Repeated corticosterone-induced activation of BLA principal neurons prevalence of extreme behavioral responders, showing a preventive role prevents the glutamatergic-induced synaptic plasticity that accompanies of corticosterone (Cohen et al., 2006, 2008). Additionally, rats showing the stress-induced anxiety-like behavior in rodents (Chattarji et al., a PTSD-like phenotype present an enhanced suppression of corticoste­ 2015). The combined findings in the beforementioned data suggest that, rone after methylprednisolone administration under basal conditions, rather than the dose, the timing of corticosterone administration is a key suggesting that the enhanced negative feedback of the HPA axis and its factor preventing stress-induced plasticity in principal neurons of the regulatory mechanisms might underlie PTSD vulnerability (Danan et al., BLA. 2021). Thus, these studies highlight that reduced HPA basal activity Altogether, these data suggest that the presence of elevated levels of and/or HPA’s blunted reaction to stress might confer increased vulner­ CORT at the time of acute stress confers protection against the detri­ ability to developing PTSD-like behaviors while corticosterone admin­ mental behaviors induced by PTSD-like animal models, through the istration could prevent the development of PTSD-related symptoms. prevention of neuronal plasticity abnormalities in critical stress- regulation areas in the brain such as the dorsal hippocampus and the 4.2. Neurobiological impact of corticosterone administration after BLA. traumatic stress exposure 5. Future directions Among all areas studied, the hippocampus and amygdalar complex appear to be crucial hubs for stress response modulation after trauma. The pathophysiology underlying HPA axis alterations in PTSD pa­ Sustained glucocorticoid levels induce long-term hippocampal alter­ tients is not well understood, but current research points to a gradual ations in neural physiology and neurotransmission, and recent research sensitization to glucocorticoid feedback leading to hypocortisolemia in a highlights that experience-induced vulnerabilities may be restored vulnerable population after stress (Schumacher et al., 2019). Therefore, through the discrete administration of compounds targeting GR or MR. traumatic experiences that involve an over-physiologic adrenergic Indeed, prepubertal (PND 26–29) administration of a GR antagonist, or response, coupled with a blunted cortisol response to stressful experi­ the overexpression of MR, restores the normal phenotype by regulating ences, might result in a stronger encoding of traumatic memories and glutamate and gamma-aminobutyric acid (GABA) transmission (Loi subjective feelings of distress. These alterations in synaptic plasticity et al., 2017). Interestingly, in adults, the nuclear factor-κB (NF-κB) in the across stress-regulator regions in the brain may eventually trigger a hippocampus plays a major role in the preventive effects of corticoste­ complex phenotype characterized by alterations in perception and rone administered after acute severe stress. In rats, extreme behavioral thoughts (Yehuda, 2002). responders present an upregulation of p50 and p65 NF-κB in the hip­ Pharmacological glucocorticoid-based interventions occurring pocampus, and this expression is normalized by post-stress administra­ shortly after a traumatic event may be the most effective approach to tion of a high dose of corticosterone, thus, showing a potential role for disrupt fear memories, by halting their consolidation, in what some the hippocampal NF-κB molecular complex in mediating the long-term authors have called the “golden hours”, namely a defined and limited effects of stressful experiences (Cohen et al., 2011). Similarly, rats temporal window when the response triggered by trauma could be exposed to cat litter that receives corticosterone treatment after stress modified (McGaugh, 2000; Zohar et al., 2011a). However, this theo­ show increased expression of hippocampal brain-derived neurotrophic retical approach may be useful for individuals with hypocortisolemic factor (BDNF) and decreased expression of postsynaptic density-95 responses toward stress but may not apply to all individuals, as gluco­ (PSD-95) compared to stressed animals which have not received the corticoids could even enhance the consolidation of fear-motivated 9 A. Florido et al. Neuropharmacology 224 (2023) 109344 behaviors in individuals who do not have a blunted HPA response. and female animals and humans. Indeed, PTSD is twice as prevalent in Research has identified plenty of risk factors for PTSD, although indi­ women than in men (Bangasser and Valentino, 2014). Thus, it must be vidual risk prediction remains elusive due to the lack of clinical studies taken into consideration of the possible sex differences in vulnerability and the heterogeneity of their nature. Current models and analyses of and response to the treatment for future studies. PTSD risk disregard interindividual differences, and they oftentimes Overall, the existing studies that evaluate the efficacy of homogenize groups of patients suffering from PTSD after several types of glucocorticoid-based therapy for preventing PTSD are encouraging. traumatic experiences, that differ in intensity, duration, and nature of Notwithstanding, the specific mechanisms that mediate this effect and the stressors (e.g., motor vehicle accidents, war combat, sexual abuse) the population that might benefit from it remain elusive for research, (Qi et al., 2016). Analyses focused on individual symptom trajectories due to methodological differences and gaps in translational studies. and the use of algorithms may help to make better treatment predictions Further studies are warranted to explore the effectiveness of this inter­ in patients at identified risk of PTSD after a stressful experience (Gal­ vention, the specific populations of interest for this treatment based on atzer-Levy et al., 2014; Schultebraucks et al., 2020). Indeed, these individual differences, and to identify the neurobiological mechanisms studies appear to be crucial to identifying the specific traits that make a underpinning its efficacy. population more likely to positively respond to glucocorticoid-based therapies. Declarations of competing interest Although evidence for a beneficial effect of glucocorticoids for PTSD prevention or decreased severity of PTSD symptoms has been reported None. (onset and symptom intensity), the quality of the evidence is moderate, with most of the studies having a considerable risk of bias and relying on Data availability small samples. Still, it is unknown whether universal prevention of PTSD with hydrocortisone is feasible given the adverse effects profile of the No data was used for the research described in the article. drug, the constrained dosing during the “golden hours” and the patients’ agreement (Astill Wright et al., 2019). It is still necessary to frame the Acknowledgements limitations of this intervention since some studies have found that glucocorticoid-based administration has only been beneficial for a sub­ RA was supported by RETOS-MINECO PID2020-112705RB-I00 set of patients (Delahanty et al., 2013; Kok et al., 2016; Shaked et al., FEDER funds, ERANET-Neuron JTC 2019 ISCIII AC19/00077 and 2021). Of note, the studies reported on glucocorticoid-based pharma­ Fundación Koplowitz. LPC was supported by FJC2018-037958-I and cotherapy for the treatment of PTSD remain controversial. Future IJC2020-045314-I from MCIyU. ERV was supported by the BES-2017- studies that include larger sample sizes, homogeneous methods, and 080870 FPI-2017 fellowship from MINECO. MC is funded by a Sara consider individual data and symptom trajectories may be able to arrive Borrell postdoctoral contract [CD20/00189] from the ISCIII. SM was at stronger conclusions. supported by the Swiss National Science Foundation (SNSF) [NCCR Similar to all pharmacological interventions, the use of glucocorti­ Synapsy grant: 51NF40-158776 and − 185897]. coids should be weighed against their risks since sustained glucocorti­ coid use carries possible side effects like insomnia, edema, hypomania, References electrolyte imbalances, or suppression of the HPA axis (Warrington and Bostwick, 2006; Williams, 2018). 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