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Affects approximately 30% of patients with major depression (10-12 million people in the US alone). Defined as failure to respond adequately to 2 or more antidepressant trials.
Third-line antidepressants, augmentation strategies (lithium, thyroid hormone, atypical antipsychotics), ECT, TMS, VNS. Response rates decline with each failed trial.
IV ketamine (0.5mg/kg, rapid onset within hours) is the most established. Psilocybin-assisted therapy shows remarkable results in Phase 2 trials with lasting effects from just 1-2 sessions. Both work through distinct mechanisms from traditional antidepressants.
Ketamine: 50-70% response within hours (Zarate et al., 2006). Psilocybin: 71% response, 54% remission at 4 weeks (Davis et al., 2021). Both show rapid onset compared to weeks for SSRIs.