R (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine

Growing evidence implicates glutamatergic neurotransmission through the N-methyl-D-aspartate (NMDA) receptor in the neurobiology and treatment of major depressive disorder (MDD). Ketamine, an NMDA receptor antagonist given clinically as the racemic mixture RS (±)-ketamine, produces rapid antidepressant effects in patients with MDD including treatment-resistant cases. The two stereoisomers differ pharmacologically: S (+)-ketamine has about fourfold greater affinity for the NMDA receptor and greater anaesthetic and psychotomimetic potency compared with R (−)-ketamine, but most clinical studies have used the racemate so the relative antidepressant contributions of each isomer remain unclear. Zhang and colleagues set out to compare the antidepressant-like effects of the individual ketamine isomers in an animal model. Using juvenile mice that had been exposed neonatally to dexamethasone (DEX) — a paradigm the investigators previously reported to produce depression-like behaviour — the study examined whether R- and S-ketamine differ in acute and sustained effects on several behavioural assays relevant to depression. The aim was to determine potency and duration of effect for each isomer after a single administration.

The study used male and female ICR mice, housed under standard laboratory conditions with food and water ad libitum; ethical approval was obtained from Chiba University’s Animal Care and Use Committee. Neonatal treatment involved intraperitoneal (i.p.) injections of dexamethasone (DEX) on postnatal days 1–3 at doses of 0.5, 0.3 and 0.1 mg/kg respectively, or equivalent volumes of saline, following the team’s previously described protocol for producing juvenile depression-like behaviour. R- and S-ketamine hydrochloride were prepared by recrystallisation of the racemate and their purity was checked by chiral HPLC. On juvenile day 36, mice received a single i.p. injection of vehicle (saline 10 ml/kg) or R- or S-ketamine at 10 mg/kg (dose expressed as the hydrochloride). Behavioural testing included locomotion (LMT), tail suspension test (TST), forced swimming test (FST) and 1% sucrose preference test (SPT); the TST observer was blinded to group assignment. The LMT recorded cumulative movement for 60 min, the TST recorded immobility over 10 min, FST immobility was scored over 6 min using automated apparatus, and sucrose preference was measured after habituation and a 1 h two-bottle test following 4 h deprivation. Statistical analysis used one-way ANOVA followed by LSD post hoc tests, with results reported as mean ± standard error of the mean (S.E.M.) and significance set at p < 0.05. The extracted text does not clearly report group sample sizes in the Methods section.

Locomotor activity did not differ between groups after a single administration of either isomer (one-way ANOVA: F(3,39) = 0.260, p = 0.854), indicating no gross motor confound for subsequent behavioural assays. For acute antidepressant-like effects, one-way ANOVA showed significant group differences in immobility for both the TST and FST (TST: F(3,32) = 9.231, p = 0.001; FST: F(3,30) = 5.618, p = 0.004). Both R- and S-ketamine significantly attenuated the DEX-induced increases in immobility when tested approximately 27–29 h after injection. R-ketamine showed slightly greater potency than S-ketamine at these early timepoints, but that difference was not statistically significant. Sucrose preference analysis also indicated a group effect (F(3,26) = 3.951, p = 0.016). Both isomers significantly reversed the reduced 1% sucrose preference seen in DEX-treated juvenile mice when measured 52 h after ketamine injection. To assess durability, the investigators retested immobility at day 7 post-administration: ANOVA again showed group effects (TST: F(3,33) = 4.764, p = 0.007; FST: F(3,31) = 7.956, p < 0.001). At day 7, R-ketamine but not S-ketamine significantly reduced the increased immobility produced by neonatal DEX exposure. The difference between R- and S-ketamine at this later timepoint reached statistical significance (TST: p = 0.011; FST: p = 0.005).

Zhang and colleagues interpret these findings to mean that a single 10 mg/kg dose of either R- or S-ketamine produces rapid antidepressant-like effects in juvenile mice that had been exposed to neonatal DEX, with effects evident around 27–29 h after dosing. Crucially, R-ketamine exhibited longer-lasting activity, with antidepressant-like effects still present at day 7 after a single injection while S-ketamine’s effects had dissipated. The investigators argue that the longer duration of R-ketamine is unlikely to be explained by pharmacokinetics alone, since both isomers would be expected to be cleared by day 7; they therefore discuss alternative mechanisms. Prior work cited by the authors links neonatal DEX exposure to alterations in glutamatergic amino acids and to NMDA receptor–related changes, and the team note that an NMDA GluN2B antagonist prevented the depression-like phenotype in this model, supporting involvement of glutamatergic transmission. Human PET data referenced in the discussion suggest that psychotomimetic, hyperfrontal metabolic effects are primarily produced by S-ketamine, whereas R-ketamine tends to decrease cerebral metabolic rates and produce relaxation without psychosis. R-ketamine is also reported to have weak affinity for the sigma-1 receptor chaperone, and the authors propose that actions at non-NMDA targets — including sigma-1, opioid receptors, voltage-dependent ion channels or α7 nicotinic acetylcholine receptors — or activity of ketamine metabolites (for example RS-dehydronorketamine acting on α7 receptors) might contribute to its sustained antidepressant effects. Clinical observations and small open-label reports are noted as consistent with a possibility that R-ketamine may have greater antidepressant potency than S-ketamine, but the authors acknowledge these human data are indirect and that direct comparisons in patients are lacking. They conclude that R-ketamine produces rapid and longer-lasting antidepressant-like effects in this juvenile DEX model and appears to lack the psychotomimetic side effects associated with S-ketamine, recommending further mechanistic and translational studies to clarify the molecular basis and clinical relevance of the isomer-specific effects.