2023 FDA Science Forum
The Neurotoxic Potential of a Single Dose of Ketamine in Adolescent and Adult Rats
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Contributing OfficeNational Center for Toxicological Research
Abstract
In 2019, FDA approved esketamine (SPRAVATO®), an enantiomer of the dissociative anesthetic ketamine, for treatment-resistant depression and for depressive symptoms associated with acute suicidal ideation or behavior in adults. Ketamine is known to cause age-dependent neurotoxicity in rat brain. Data from published literature indicate that a single dose of ketamine can result in neuronal necrosis in the sexually mature adult rat brain and apoptosis in the developing rat brain (equivalent to late gestation up to three years of age in humans). Even though data are limited, scientists have speculated that the period between early childhood until sexual maturation is considered safe. Addressing this knowledge gap will reduce uncertainty about how ketamine can be safely used in children up to adolescent age. In this study, we treated male and female rats with a single dose of ketamine (50, 75, 100 mg/kg, s.c.), a positive control (2 mg/kg MK-801, i.p.), or vehicle on postnatal day (PD) 21, 30, 35, or 90. Animals were sacrificed 72 hours later and brains were collected for histopathological evaluation. The brain was sectioned to include the olfactory bulb, fronto-parietal cortex, mid-parietal cortex and thalamus, mid-brain, and cerebellum. The resulting sections were stained with H&E and evaluated for signs of neurodegeneration. Necrotic neurons were observed after treatment with MK-801 in both male and female animals at PND 30, 35, and 90. However, ketamine (100 mg/kg, s.c.) only caused necrosis in the retrosplenial cortex of female rats dosed on PND 90 (N=3/12). These data show that younger animals are less vulnerable to the neurotoxic effects of ketamine as assessed by H&E at the tested doses. These findings provide supportive information to determine if the speculated “protected period” in young animals is driven by a decreased sensitivity to the toxic effects of ketamine or age-related differences in pharmacokinetics. These data will help us determine safe parameters for the use of ketamine in the pediatric population.
