Detrimental Side Effects of Repeated Ketamine Infusions in the Brain

To the Editor: It was with great interest that I read the recent article by Singh et al. (1) about the rapid and sustained antidepressant effects of multiple intravenous infusions (two or three times weekly) of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine (administered at 0.5 mg/kg of body weight for 40 minutes) in patients with treatment-resistant depression. The results showed response rates of 68.8% for twice-weekly dosing and 53.8% for thrice-weekly dosing at day 15, suggesting that a twice-weekly initiation treatment regimen appears to be sufficient as an initial repeated-dose strategy. Treatment-emergent adverse events (e.g., headache, anxiety, dissociation, nausea, and dizziness) were higher in both ketamine groups compared with the respective placebo groups. Acute transient psychotomimetic and dissociative symptoms were observed, which usually resolved within 2 hours after each infusion. The intensity of dissociative symptoms diminished with repeated dosing.

Ketamine (or RS-ketamine) is a racemic mixture containing equal parts of R-ketamine and S-ketamine (esketamine). Esketamine has an approximately fourfold greater affinity for the NMDA receptor than R-ketamine (2). Furthermore, the number of undesirable psychotomimetic side effects produced by esketamine is approximately three to four times higher than the number produced by R-ketamine (2), and it is well known that the psychotomimetic effects of ketamine are associated with NMDA receptor antagonism. Interestingly, we reported in rodent models of depression that R-ketamine shows greater potency and longer-lasting antidepressant effects than esketamine (3, 4). Recently, we reported that the repeated, intermittent administration (once weekly for 8 weeks) of esketamine, but not R-ketamine, caused loss of parvalbumin immunoreactivity in the prefrontal cortex of mouse brain (5). Because the loss of parvalbumin immunoreactivity in the prefrontal cortex may be associated with psychosis and γ-oscillation deficits in schizophrenia, it is possible that repeated infusions of esketamine or ketamine may have long-lasting detrimental side effects in the human prefrontal cortex. Further studies of the detrimental side effects of repeated ketamine infusions over longer periods are needed.

In conclusion, it is likely that R-ketamine would be an alternative antidepressant for ketamine because the repeated administration of R-ketamine may be free of side effects.