In a phase 3 trial across seven mood disorders centers in Australia and New Zealand, subcutaneous racemic ketamine was tested against midazolam for treatment-resistant depression. With flexible dosing (0.5–0.9 mg/kg), ketamine led to a 19.6% remission rate compared to 2.0% for midazolam, a significant difference. Fixed dosing (0.5 mg/kg) showed no difference. Acute side effects, such as psychotomimetic effects and blood pressure increases, resolved within two hours. The subcutaneous route proved practical and feasible.
Ketamine and esketamine can rapidly relieve depression that does not respond to standard treatments, but how they work at the molecular level is not well understood. A systematic review of 12 studies examined changes in gene activity (RNA expression) after ketamine or esketamine treatment in people with depression or in human cells grown in the lab. The studies found that these drugs alter the activity of genes involved in brain cell communication, immune regulation, and the brain's ability to adapt and change. However, no single consistent marker in the blood was identified across studies. The findings suggest that mapping gene activity patterns could help reveal how these treatments work and identify who might benefit most, though more research is needed.
Intranasal S-ketamine (Spravato) can be safely and effectively administered in an acute psychiatric emergency setting to treat depressive crises in patients with treatment-resistant major depressive disorder who have severe suicidal ideation. In a case series of 10 patients (70% female, mean age 49.5 years), average MADRS scores dropped from 37 pre-treatment to 18 post-treatment, and BDI scores dropped from 39 to 24. Side effects such as dissociation were short-lived.