Characterizing the therapeutical use of ketamine for adolescent rats of both sexes: Antidepressant-like efficacy and safety profile.

Ketamine, approved for treatment-resistant depression in adults, shows potential as an antidepressant for adolescents but with sex-specific dose requirements and safety concerns. In rats, a single dose of 5 mg/kg produced antidepressant-like effects in females and 10 mg/kg in males, while 7-day treatment extended efficacy to lower doses. Safety assessments revealed psychomotor sensitization in adolescent females at the antidepressant dose and addiction liability in adult males re-exposed to ketamine after adolescent treatment. These findings indicate that ketamine's antidepressant effects in adolescence are dose- and sex-dependent, but the observed safety risks warrant caution before clinical translation.

Study at a glance

Abstract

While ketamine was approved for treatment-resistant depression in adult patients, its efficacy and safety profile for adolescence still requires further characterization. In this context, prior preclinical studies have shown that sub-anesthetic doses of ketamine during adolescence exert antidepressant-like effects in rodents in a dose- and sex-dependent manner. However, additional studies evaluating the short- and long-term safety profile of ketamine at the doses necessary to induce antidepressant-like effects are needed. The present study aimed at validating the dose- and sex-dependent antidepressant-like responses of adolescent ketamine while evaluated its safety profile in rats of both sexes. To do so, ketamine was administered (1, 5 or 10 mg/kg; vs. vehicle; 1 vs. 7 days) during adolescence in naïve or early-life stressed (i.e., maternal deprivation) rats of both sexes. Antidepressant-like responses were scored in the forced-swim or novelty-suppressed feeding tests, and safety was evaluated by measuring psychomotor- and reinforcing-like responses induced by ketamine. In addition, long-term safety was assessed in adulthood through cognitive performance, or addiction liability (induced by ketamine re-exposure in rats treated with ketamine in adolescence). The main results validated the potential use of ketamine as an antidepressant for adolescence, but at different dose ranges for each sex. However, some safety concerns emerged in adolescent female rats (i.e., signs of sensitization at the dose used as antidepressant) or adult male rats (i.e., addiction liability when re-exposed to ketamine in adulthood), suggesting that caution and further research are needed before ketamine could be safely used in the clinic as an antidepressant for adolescents.