Depression affects approximately 5% of adults worldwide, and treatment-resistant depression represents a significant clinical challenge. About one-third of people with depression do not respond to current medications, with standard treatments either providing no benefit or improving symptoms only temporarily. People are considered to have treatment-resistant depression if they have not responded to adequate doses of two different antidepressants taken for a sufficient duration, typically around six weeks.
New Pharmacological Approaches
The FDA approval of esketamine (brand name Spravato) in 2019 marked the first approval of a new antidepressant class in many years. Esketamine targets the glutamate system, the major excitatory neurotransmitter in the brain, working differently from traditional antidepressants that target serotonin or norepinephrine. Ketamine can offer rapid relief for treatment-resistant depression, with some people potentially feeling benefits within approximately 40 minutes, contrasting with traditional SSRIs requiring weeks to take effect.
Compass Pathways announced that its phase 3 trial of psilocybin-based compound COMP006 for treatment-resistant depression achieved its primary endpoint in February. The company expects to complete a New Drug Application submission in Q4 of 2026. Research has shown that psilocybin reduces activity in the medial prefrontal cortex and decreases connections to the posterior cingulate cortex, potentially removing constraints of the internal “self” and reducing depression symptoms.
Other recently approved antidepressants include Auvelity, combining dextromethorphan and bupropion, approved in 2022 and thought to provide faster-acting relief within one week. Zuranolone, approved in 2023 for postpartum depression, requires only a 2-week course with effects sustained beyond that period, with some people feeling better within two to three days.
Next-Generation Approaches
Next-generation neuroplastogens separate the therapeutic effects of psychedelics from their hallucinogenic properties, potentially enabling conventional clinical settings and integration into existing healthcare systems. Companies including Enveric Biosciences and Elkedonia are developing these compounds, though both remain in preclinical stages. A Trump executive order in April aimed at accelerating research, regulatory review, and access to psychedelic drugs to treat mental health conditions has driven renewed investor and industry attention.
This article is an AI-assisted summary. All facts and figures are drawn from the original report: https://www.labiotech.eu/in-depth/new-antidepressants-treatment-resistant-depression/