Nitrous oxide (N2O) shows promise as a fast-acting antidepressant for treatment-resistant depression (TRD), especially in older adults. Its mechanisms may include NMDA receptor antagonism and cerebral vasodilation, which could improve drug delivery and address resistance linked to poor cerebrovascular function. N2O is not metabolized by the kidney or liver, potentially making it safer for older adults. Review of available data on efficacy, safety, and pathophysiology is presented, along with results showing reduced anterior cingulate cortex connectivity and increased brain tissue pulsations during successful N2O treatment. Ongoing RCTs in older adults with TRD and neurocognitive disorders are discussed.
Ketamine, particularly intranasal esketamine, is FDA-approved for treatment-resistant depression, but evidence in older adults remains scarce. Two cases of older individuals with treatment-resistant depression treated with intranasal ketamine are described: one improved, one did not. The scarce available literature suggests ketamine is well tolerated and effective in the geriatric population, with remission rates of 46.5%, 57%, and 69.5% reported in three separate studies. The presentation reviews ketamine's mechanism of action as a novel antidepressant, the mixed evidence for its role in late-life treatment-resistant depression, and practical aspects of running a ketamine clinic.