Ketamine and esketamine are the first non-monoamine-based antidepressants with rapid-onset efficacy for adults with treatment-resistant depression, offering hope to those who do not recover fully with standard antidepressants. However, concerns remain about their safety, tolerability, and appropriate placement in treatment algorithms. An international group of mood disorder experts synthesizes evidence on efficacy, safety, and tolerability, and provides guidance for clinical implementation, including practice parameters at point of care. Areas of consensus and future research directions are discussed.
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.