A randomized placebo-controlled trial tested whether a fixed low dose of oral esketamine (30 mg three times daily) could reduce depression severity in patients with treatment-resistant depression. Over six weeks, the drug showed no benefit compared to placebo on the Hamilton Depression Rating Scale. Dizziness and sleep hallucinations were more common with esketamine. In an open-label extension phase where doses were individually titrated up to 3.0 mg/kg twice weekly, depressive symptoms decreased substantially. The findings suggest that fixed low-dose oral esketamine is ineffective, but individually adjusted higher doses may hold promise for treatment-resistant depression.
Oral esketamine, taken twice weekly for six weeks at doses from 0.5 to 3 mg/kg, reduced depressive symptom severity in adults with severe treatment-resistant depression who had not benefited from an average of 8.1 prior antidepressant trials and, in 63% of cases, electroconvulsive therapy. Hamilton Depression Rating Scale scores dropped from 21.2 to 15.8. Nearly half of participants achieved a clinically meaningful improvement, 26.8% responded, and 15.6% remitted. Side effects were common but well tolerated, with a 7.6% dropout rate and no significant urinary or cognitive adverse effects. Treatment continued beyond six weeks in 45.9% of participants to maintain gains.
Oral esketamine can be an effective and well-tolerated treatment for treatment-resistant depression (TRD), but about half of those treated do not respond. This study tested whether sociodemographic and clinical features, including depressive symptoms and treatment resistance, could predict how much depressive symptoms would improve in 131 TRD patients receiving individually adjusted oral esketamine doses (0.5 mg/kg to 3 mg/kg) twice weekly for six weeks. Machine learning models—linear regression, elastic net, and random forest—failed to predict symptom change above chance. The findings suggest that oral esketamine may work similarly across the TRD population, regardless of treatment-resistance levels.
This preregistration describes an update and extension of a meta-analysis examining ketamine and esketamine for adults with treatment-resistant major depressive disorder. The project is nested within a larger network meta-analysis of next-step strategies for treatment-resistant depression. It restricts interventions to ketamine and esketamine regimens versus placebo, structures outcomes into three time windows (24–72 hours, 1–3 weeks, and 4–12 weeks), and pools results using pairwise random-effects meta-analyses rather than network meta-analysis due to expected lack of direct comparisons between treatment nodes. Short-term outcomes will be extracted from longer-term trials. Subgroup and meta-regression analyses are exploratory.