When several FDA-approved pharmacotherapies fall short and produce a suboptimal response, clinicians can resort to other treatment options known to have a higher efficacy than oral antidepressants. These include electroconvulsive therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation. Other on-label options include adjunctive therapy with one of the approved second-generation antipsychotic agents or with adjunctive esketamine.
But if the patient still does not improve, one of many emerging off-label treatment options may work. One of the exciting new discoveries is the hallucinogen psilocybin, whose mechanism of action is truly unique. Unlike standard antidepressant medications, which modulate neurotransmitters, psilocybin increases the brain’s network flexibility, decreases the modularity of several key brain networks (especially the default-brain network, or DMN), and alters the dark and distorted mental perspective of depression to a much healthier and optimistic outlook about the self and the world.8 Such novel breakthroughs in the treatment of severe depression will shed some unprecedented insights into the core neurobiology of depression, and may lead to early intervention and prevention.
As the saying goes, all roads lead to Rome. Psychiatric clinicians should rejoice that there are abundant approaches and therapeutic mechanisms to relieve their severely melancholic (and often suicidal) patients from the grips of this disabling and life-altering brain syndrome.