A small pilot clinical trial conducted in China has revealed promising results for esketamine as a potential treatment for Rett syndrome symptoms, particularly in improving behavioral dysfunction and hand function in pediatric patients.
Clinical Trial Design and Patient Population
The Phase 1 pilot study (NCT06199700) enrolled three young girls with Rett syndrome, aged 9-10 years, who received five weekly intravenous esketamine infusions at a dose of 0.25 mg/kg. The participants exhibited typical Rett syndrome characteristics, including mood issues, stereotypic hand behaviors, and limited hand functionality.
Key Findings and Clinical Outcomes
Two of the three participants demonstrated notable clinical improvements following esketamine treatment. Researchers observed significant positive changes in both mood and behavior, with patients displaying increased smiling and social engagement. Particularly striking was the reduction in hand stereotyping—a characteristic symptom of Rett syndrome—during infusions, with effects lasting for one to two hours post-treatment.
The efficacy assessment, conducted through various Rett-related questionnaires completed by both clinicians and caregivers, showed encouraging results. Video electroencephalogram (VEEG) monitoring revealed improvements in the posterior dominant rhythm among responding patients, indicating positive changes in brain activity patterns typically disrupted in Rett syndrome.
Functional Improvements and Daily Activities
Perhaps most notably, patients exhibited previously unseen behaviors that suggested improved hand function. These included pushing away unwanted food, touching parents' faces, and holding objects independently—activities that hadn't been observed in years, according to caregivers.
Safety Profile and Tolerability
The treatment demonstrated a favorable safety profile, with no severe adverse events reported. Side effects were minimal and manageable, primarily consisting of temporary nausea during infusions in two patients and possible nausea-related irritability in the third. Patients typically returned to their usual activities within an hour post-infusion.
Scientific Context and Mechanism
Esketamine, a chemical relative of ketamine, works by blocking NMDA receptors involved in glutamate signaling. This mechanism is particularly relevant for Rett syndrome, as research has shown abnormalities in NMDA receptor levels and glutamate signaling in affected individuals.
Future Research Directions
While the small sample size limits broad conclusions, the researchers suggest that these results warrant further investigation. They propose exploring different dosages and administration routes, such as nasal sprays, to potentially enhance therapeutic benefits while minimizing side effects.
The study's findings are particularly significant given that a recent Phase 2 trial of oral ketamine in the United States showed no efficacy in treating Rett syndrome symptoms, highlighting the potential importance of drug formulation and delivery method in treatment success.
