When people with severe depression that hasn’t responded to regular antidepressants get a nasal spray called esketamine along with their usual meds, they tend to feel a little better after a few weeks—about as much as if they added a different type of psychiatric pill.

Whether intranasal esketamine plus standard antidepressants leads to a small reduction in depression symptoms compared to placebo plus standard antidepressants in adults with treatment-resistant major depressive disorder, measured by standardized depression scales at weeks 2–4, with effect sizes between 0.15 and 0.23.

Whether the reduction in depression symptoms from intranasal esketamine plus antidepressants is non-inferior to that from atypical antipsychotic augmentation plus antidepressants in adults with treatment-resistant MDD, with both groups showing effect sizes between 0.15 and 0.23 at weeks 2–4.

Whether the pooled effect size of intranasal esketamine as adjunct to antidepressants across multiple RCTs falls within the range of 0.15–0.23 at weeks 2–4 and is comparable to the pooled effect size of atypical antipsychotic augmentation.

Whether real-world use of intranasal esketamine as an adjunct to antidepressants is associated with a small reduction in depression symptoms (effect size 0.15–0.23) in adults with treatment-resistant MDD over 2–4 weeks, compared to those receiving antipsychotic augmentation.

Whether patients who received intranasal esketamine as an adjunct to antidepressants were more likely to show a small reduction in depression symptoms (effect size 0.15–0.23) at weeks 2–4 compared to those who received antipsychotic augmentation.