Intranasal esketamine (Spravato) rapidly relieves depression symptoms—often within hours—and improves remission and response rates in treatment-resistant depression (TRD) and severe major depressive disorder. Unlike conventional antidepressants, it works by blocking NMDA receptors to promote synaptogenesis and neuroplasticity. Its use is associated with a very low incidence of treatment-emergent sexual dysfunction (less than 1% of patients), a common side effect of SSRIs and SNRIs. However, esketamine can cause dissociative symptoms and blood pressure changes, and its administration requires in-clinic monitoring under a REMS program. Despite these limitations, it offers a valuable option for patients who do not respond to standard therapies.
Psilocybin, a naturally occurring psychedelic compound, shows promise as a treatment for major depressive disorder, especially when traditional therapies fail. Evidence from clinical studies between 2014 and 2024 indicates that psilocybin acts on serotonin 5-HT2A receptors, enhancing neuroplasticity and brain connectivity to produce rapid and sustained symptom relief. However, its classification as a Schedule I substance in many countries and societal stigma have restricted research and use. Overcoming regulatory barriers, conducting larger and more diverse studies, and establishing long-term safety and efficacy data are critical for integrating psilocybin into mainstream mental health care.