Exploring pharmacological options for adolescent depression: a preclinical evaluation with a sex perspective

There is an urgent need for developing novel pharmacological treatment options for adolescent depression, and to ensure an optimal translational outcome to the clinic, sex should be included as a biological variable in preclinical studies. In this context, the present study compared the antidepressant-like potential of ketamine and cannabidiol, with the clinical standard fluoxetine, in adolescent rats exposed to maternal deprivation (as a model of early-life stress), while including a sex perspective. Moreover, changes in drug efficacy over time were evaluated by re-exposing rats to the same dose regimens during adulthood. Antidepressant-like responses were scored through a battery of distinctive tests (forced-swim, novelty-suppressed feeding, and sucrose preference) across time. The main results proved an antidepressant-like potential for ketamine and cannabidiol in adolescent rats, although their efficacy was dependent on sex and prior stress exposure, as well as on treatment length and the behavioral feature analyzed. In general, while all tested antidepressants in male rats improved certain affective-like features, female rats were mainly unresponsive to the treatments performed (except for certain benefits induced by ketamine), demonstrating the need for further characterizing proper treatments for this particular sex. Moreover, when rats were re-exposed in adulthood to the same drug regimens as in adolescence, a drop in efficacy was observed. These findings may have translational ramifications in that ketamine or cannabidiol could be moved forward as antidepressants for the adolescent depressed population, but not before further characterizing their potential long-term safety and/or beneficial vs. harmful effects for both sexes.

Automated summary

There is an urgent need to develop new pharmacological treatments for adolescent depression, with inclusion of sex as a biological variable in preclinical studies. This study compared ketamine and cannabidiol with fluoxetine in adolescent rats exposed to early-life stress, incorporating a sex perspective. The main findings indicated an antidepressant-like potential for ketamine and cannabidiol in adolescent rats, dependent on sex, stress exposure, treatment length, and behavioral features. Male rats showed improvement in affective-like features with all tested antidepressants, while female rats were mostly unresponsive. Re-exposure to the same drug regimens in adulthood resulted in decreased efficacy. Further characterization of the long-term safety and effects for both sexes is needed before ketamine or cannabidiol can be considered as antidepressants for adolescents.