Novel rapid treatment options for adolescent depression.

There is an urgent need for novel fast-acting antidepressants for adolescent treatment-resistant depression and/or suicidal risk, since the selective serotonin reuptake inhibitors that are clinically approved for that age (i.e., fluoxetine or escitalopram) take weeks to work. In this context, one of the main research lines of our group is to characterize at the preclinical level novel approaches for rapid-acting antidepressants for adolescence. The present review summarizes the potential use in adolescence of non-pharmacological options, such as neuromodulators (electroconvulsive therapy and other innovative types of brain stimulation), as well as pharmacological options, including consciousness-altering drugs (mainly ketamine but also classical psychedelics) and cannabinoids (i.e., cannabidiol), with promising fast-acting responses. Following a brief analytical explanation of adolescent depression, we present a general introduction for each therapeutical approach together with the clinical evidence supporting its potential beneficial use in adolescence (mainly extrapolated from prior successful examples for adults), to then report recent and/or ongoing preclinical studies that will aid in improving the inclusion of these therapies in the clinic, by considering potential sex-, age-, and dose-related differences, and/or other factors that might affect efficacy or long-term safety. Finally, we conclude the review by providing future avenues to maximize treatment response, including the need for more clinical studies and the importance of designing and/or testing novel treatment options that are safe and fast-acting for adolescent depression.

Evaluating the daily modulation of FADD and related molecular markers in different brain regions in male rats.

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.

Sex differences in the antidepressant-like response and molecular events induced by the imidazoline-2 receptor agonist CR4056 in rats.

In searching for novel targets to design antidepressants, among the characterized imidazoline receptors (IR), I2 receptors are an innovative therapeutical approach since they are dysregulated in major depressive disorder and by classical antidepressant treatments. In fact, several I2 agonists have been characterized for their antidepressant-like potential, but the results in terms of efficacy were mixed and exclusively reported in male rodents. Since there are well-known sex differences in antidepressant-like efficacy, this study characterized the potential effects induced by two I2 drugs, CR4056 (i.e., most promising drug already in phase II clinical trial for its analgesic properties) and B06 (a compound from a new family of bicyclic α-iminophosphonates) under the stress of the forced-swim test in male and female rats exposed to early-life stress. Moreover, some hippocampal neuroplasticity markers related to the potential effects observed were also evaluated (i.e., FADD, p-ERK/ERK, mBDNF, cell proliferation: Ki-67 + cells). The main results replicated the only prior study reporting the efficacy of CR4056 in male rats, while providing new data on its efficacy in females, which was clearly dependent on prior early-life stress exposure. Moreover, B06 showed no antidepressant-like effects in male or female rats. Finally, CR4056 increased FADD content and decreased cell proliferation in hippocampus, without affecting p-ERK/t-ERK ratio and/or mBDNF content. Interestingly, these effects were exclusively observed in female rats, and independently of early-life conditions, suggesting some distinctive molecular underpinnings participating in the therapeutic response of CR4056 for both sexes. In conjunction, these results present CR4056 with an antidepressant-like potential, especially in female rats exposed to stress early in life, together with some neuronal correlates described in the context of these behavioral changes in females.