Early administration of S-Ketamine (on day 1) after trauma significantly improves PTSD symptoms in rodent models, particularly impaired fear extinction, while late administration (day 7) does not. The firing and burst rates of dopamine neurons in the ventral tegmental area (VTA) decrease after PTSD modeling and are restored only by early S-Ketamine. These VTA dopamine neurons respond to conditioned stimuli and help replace aversive memory encoding during fear extinction. Inhibiting the VTA-to-orbitofrontal cortex (OFC) pathway blocks S-Ketamine's therapeutic effect. A non-invasive brain stimulation targeting the OFC sensitizes cortical dopaminergic transmission and extends the effective time window of S-Ketamine for anti-PTSD treatment.
A single intravenous dose of (R)-ketamine hydrochloride, ranging from 10.0 mg to 180 mg, was safe and well tolerated in healthy Chinese subjects. Adverse events were temporary and resolved without treatment. The peak plasma concentrations of (R)-ketamine and its metabolite (R)-norketamine increased roughly in proportion to the dose, with average peak levels ranging from 56.0 to 1424 ng/mL and 27.7 to 491 ng/mL, respectively. These results support further clinical studies of this rapid-acting antidepressant for treatment-resistant depression.