A single 96-hour infusion of ketamine, co-administered with clonidine, is well tolerated and produces a rapid and sustained antidepressant response in over 50% of adults with treatment-resistant depression. In an open-label study of 23 adults, depressive symptoms dropped markedly from an average MADRS score of 29 at baseline to 9 one day after infusion, and remained reduced at 2 weeks (13) and 8 weeks (15). Brain imaging showed that the infusion normalized overconnectivity in the limbic system and between the subgenual anterior cingulate cortex and the default mode network, with response-dependent and treatment-dependent connectivity changes.
Psilocybin-assisted psychotherapy shows rapid and sustained antidepressant effects for individuals with major depressive disorder and treatment-resistant depression. This review covers the history, pharmacology, and proposed mechanism of psilocybin, and describes several published studies from the last decade demonstrating its efficacy and safety. It also discusses limitations and barriers in current psychedelic research, contextualizing results within the current treatment landscape and the pathophysiology of depression.