Sandra Ledesma-Corvi’s research while affiliated with University of the Balearic Islands and other places

While ketamine is already approved for treatment resistant depression in adult patients, its efficacy and safety profile for its use in adolescence still needs further investigations. Preclinical studies proved dose- and sex-dependent effects induced by ketamine during adolescence, but few studies have evaluated the short- and long-term safety profile of ketamine at the doses necessary to induce its antidepressant-like effects. The present study aimed at evaluating the antidepressant-like effects of ketamine (1, 5 or 10 mg/kg; vs. vehicle; 1 vs. 7 days) during adolescence in naive or early-life stressed (i.e., maternal deprivation) rats of both sexes in the forced-swim or novelty-suppressed feeding tests. Safety was evaluated by measuring the psychomotor- and reinforcing-like responses induced by adolescent ketamine. In addition, long-term safety was evaluated in adulthood at the level of cognitive performance, or addiction liability (induced by a challenge dose of ketamine in rats treated with adolescent ketamine). The main results reinforced the potential for ketamine as an antidepressant for adolescence, but at different dose ranges for each sex. However, some safety concerns emerged for adolescent female rats (i.e., signs of sensitization at the dose used as antidepressant) and adult male rats (i.e., addiction liability when re-exposed to ketamine in adulthood), suggesting the need for caution and further research before moving forward the use of ketamine as an antidepressant for adolescence.

Background The aging process causes anatomical and physiological changes that predispose to the development of late-life depression while reduces the efficacy of classical antidepressants. Novel fast-acting antidepressants such as ketamine might be good candidates to be explored in the context of aging, especially given the lack of previous research on its efficacy for this age period. Thus, the aim of the present study was to characterize ketamine’s effects in older rats. Methods The fast-acting (30 min) and repeated (7 days) antidepressant-like effects of ketamine (5 mg/kg, ip ) were evaluated in 14-month-old single-housed rats through the forced-swim and novelty-suppressed feeding tests. In parallel, the modulation of neurotrophic-related proteins (i.e., mBDNF, mTOR, GSK3) was assessed in brain regions affected by the aging process, prefrontal cortex and hippocampus, as well as possible changes in hippocampal cell proliferation. Results Acute ketamine induced a fast-acting antidepressant-like response in male aged rats, as observed by a reduced immobility in the forced-swim test, in parallel with a region-specific increase in mBDNF protein content in prefrontal cortex. However, repeated ketamine failed to induce antidepressant-like efficacy, but decreased mBDNF protein content in prefrontal cortex. The rate of hippocampal cell proliferation and/or other markers evaluated was not modulated by either paradigm of ketamine. Conclusions These results complement prior data supporting a fast-acting antidepressant-like effect of ketamine in rats, to further extend its efficacy to older ages. Future studies are needed to further clarify the lack of response after the repeated treatment as well as its potential adverse effects in aging.

Fas‐Associated protein with Death Domain (FADD), a key molecule controlling cell fate by balancing apoptotic versus non‐apoptotic functions, is dysregulated in post‐mortem brains of subjects with psychopathologies, in animal models capturing certain aspects of these disorders, and by several pharmacological agents. Since persistent disruptions in normal functioning of daily rhythms are linked with these conditions, oscillations over time of key biomarkers, such as FADD, could play a crucial role in balancing the clinical outcome. Therefore, we characterized the 24‐h regulation of FADD (and linked molecular partners: p‐ERK/t‐ERK ratio, Cdk‐5, p35/p25, cell proliferation) in key brain regions for FADD regulation (prefrontal cortex, striatum, hippocampus). Samples were collected during Zeitgeber time (ZT) 2, ZT5, ZT8, ZT11, ZT14, ZT17, ZT20, and ZT23 (ZT0, lights‐on or inactive period; ZT12, lights‐off or active period). FADD showed similar daily fluctuations in all regions analyzed, with higher values during lights off, and opposite to p‐ERK/t‐ERK ratios regulation. Both Cdk‐5 and p35 remained stable and did not change across ZT. However, p25 increased during lights off, but exclusively in striatum. Finally, no 24‐h modulation was observed for hippocampal cell proliferation, although higher values were present during lights off. These results demonstrated a clear daily modulation of FADD in several key brain regions, with a more prominent regulation during the active time of rats, and suggested a key role for FADD, and molecular partners, in the normal physiological functioning of the brain's daily rhythmicity, which if disrupted might participate in the development of certain pathologies.

Electroconvulsive therapy, a fast-acting option for treatment-resistant depression, is modeled at the preclinical level through the induction of electroconvulsive seizures (ECS) in rodents. Recent studies from our group proved sex- and age-differences in the antidepressant-like response elicited by ECS in rats; while an antidepressant-like response was observed in male adolescent and adult rats (although with greater efficacy in adulthood), the same parameters rendered inefficacious in females of any age. To better understand the potential sex differences taking place at the molecular level that might be mediating these behavioral disparities, we evaluated the impact of a repeated treatment with ECS (95 mA for 0.6 s, 100 Hz, 0.6 ms) in adolescent and adult rats of both sexes. Several hippocampal markers of neuroplasticity, commonly regulated by most antidepressants, such as those of neurogenesis (cell proliferation, neurogenic differentiation, long-term cell survival) or mBDNF and associated signaling (e.g., mTOR and ERK1/2) were evaluated at different time-points after treatment (1-, 8-, 15- and up to 30-days post-treatment). The main results demonstrated that ECS improved the survival rate of new cells born in the dentate gryus before treatment. Moreover, ECS increased cell proliferation and neurogenic differentiation at different times post-treatment, paired with persistent increases in mBDNF, observed long after treatment. In general, effects were different for each sex and varied with the age of the animal (adolescent vs. adulthood). The present study is the first-one to demonstrate that such persistent molecular changes induced by ECS in hippocampus, some of them observed up to 30-days post-treatment, also occurred in female rats and adolescence. Although these molecular changes could not justify the lack of ECS efficacy described by these same parameters of ECS in female rats (vs. male rats), they proposed certain beneficial effects common to both sexes, and age periods studied, opening the avenue for further studies. Based on these neurochemical effects, ECS should have displayed similar efficacies for both biological sexes. Therefore, the reason behind these disparities should be further explored to better translate efficacious treatments specific and/or personalized for each sex to the clinic.

Background: Ketamine has been recently approved to treat resistant depression; however preclinical studies showed sex differences in its efficacy. Sex steroids, such as estrogens and testosterone, both in the periphery and locally in the brain, are regarded as important modulators of these sex differences. Therefore, the present study evaluated how inhibiting the biosynthesis of estrogens with letrozole (an aromatase inhibitor) could affect the observed sex differences in ketamine's antidepressant-like-response. Methods: We performed several consecutive studies in adult Sprague-Dawley rats to evaluate potential sex differences in the antidepressant-like effects of ketamine (5 mg/kg, 7 days, i.p.), letrozole (1 mg/kg, 8 days, i.p.) and their combination (letrozole pre-treatment 3 h before ketamine). Acute and repeated antidepressant-like responses were ascertained in a series of behavioral tests (forced-swim, novelty-suppressed feeding, two-bottle choice for sucrose preference). Results: The main results proved clear sex differences in the antidepressant-like response induced by ketamine, which was observed following a repeated paradigm in adult male rats, but rendered inefficacious in female rats. Moreover, decreasing estrogens production with letrozole induced on itself an antidepressant-like response in female rats, while also increased ketamine's response in male rats (i.e., quicker response observed after only a single dose). Interestingly, both the antidepressant-like effects induced by ketamine in male rats or letrozole in female rats persisted over time up to 65 days post-treatment, suggesting long-term sex-directed benefits for these drugs. Conclusions: The present results demonstrated a sex-specific role for aromatase inhibition with letrozole in the antidepressant-like response induced by ketamine in male rats. Moreover, letrozole itself presented as a potential antidepressant for females with persistent effects over time. Clearly, the production of estrogens is key in modulating, in a sex-specific manner, affective-like responses and thus deserve further studies.