Characterizing the therapeutical use of ketamine for adolescent rats of both sexes: Antidepressant-like efficacy and safety profile.
Jordi Jornet-Plaza, Sandra Ledesma-Corvi, M Julia García-Fuster
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2025 DOI: 10.1016/j.biopha.2024.117781 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Adolescent rats of both sexes, including naïve and early-life stressed (maternal deprivation) groups |
| Intervention | Ketamine |
| Dose | 1, 5 or 10 mg/kg; vs. vehicle; 1 vs. 7 days |
| Topics | Addiction Depression Ketamine Esketamine |
| Keywords | Adolescence Cognition Depression treatment Adolescent mental health Ketamine therapy Drug safety Gender differences |
| Citations | 6 |
| Key points | Ketamine produces antidepressant-like effects in adolescent rats in a dose- and sex-dependent manner, but safety concerns—psychomotor sensitization in females and addiction liability in males—suggest caution for clinical use. |
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.
Comparable studies
Other preclinical and animal studies on ketamine for addiction, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| R-(-)-ketamine modifies behavioral effects of morphine predicting efficacy as a novel therapy for opioid use disorder. Morphine-dependent rats and mice | 2020 | Preclinical study | |
| The effects of (2R,6R)-hydroxynorketamine on oxycodone withdrawal and reinstatement. Male and female oxycodone-dependent mice | 2023 | Preclinical study | |
| Exploring ketamine's reinforcement, cue-induced reinstatement, and nucleus accumbens cFos activation in male and female long evans rats. Long Evans rats | 2024 | Preclinical experimental study | |
| Brain acid sphingomyelinase controls addiction-related behaviours in a sex-specific way. Male and female mice with forebrain ASM overexpression | 2025 | Experimental study | |
| Cannabidiol or ketamine for preventing the impact of adolescent early drug initiation on voluntary ethanol consumption in adulthood. Male and female Sprague-Dawley rats | 2024 | Preclinical study |