Ketamine, administered intravenously at subnarcotic doses, has emerged as a rapid-acting treatment for treatment-resistant depression. This historical overview traces its development, compares it with the newer esketamine nasal spray, and discusses future prospects. Intravenous ketamine infusions have shown efficacy in rapidly reducing depressive symptoms, while esketamine, a derivative, offers a more convenient nasal route but may have different efficacy and safety profiles. The article highlights the need for further research to optimize dosing, duration of effect, and long-term outcomes, as well as to understand the mechanisms underlying ketamine's antidepressant action.
Placebo effects remain a major paradox in medical research, with more data available from placebo-controlled trials than on any treatment, yet little deep analysis of how they are measured, appraised, and interpreted. This review shifts focus from clinical practice to clinical trials, examining established and emerging approaches for managing placebo effects in randomized controlled trials. It highlights three key challenges in contemporary psychiatric research: blinding and expectancy in psychedelic trials, large placebo responses in interventional psychiatry trials (device or procedure-based treatments), and the implications of overlapping neurobiological mechanisms between placebo effects and psychiatric treatments.