At least 30% of people with depression meet the common definition of treatment-resistant depression (TRD): inadequate response to two or more antidepressants despite adequate trials and adherence. Many cases are actually pseudo-resistant due to insufficient treatment or non-adherence. No consensus definition with proven predictive utility for clinical decisions exists, leading to varied prevalence estimates and inconsistent care. Intravenous ketamine and intranasal esketamine are effective for TRD. Some second-generation antipsychotics (e.g., aripiprazole, quetiapine XR) help as adjuncts in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation and electroconvulsive therapy are established effective interventions. Evidence for extending trials, switching, or combining antidepressants is mixed, and manual-based psychotherapies are not effective alone but help when added to antidepressants.
A participant in a phase 2b clinical trial of psilocybin for treatment-resistant depression experienced increased suicidal ideation and a prolonged period of severely restricted eating after administration, leading to destabilization and need for support. Despite limited improvement on depression rating scales, the participant found the experience helpful and made beneficial life changes. The case suggests psilocybin can temporarily worsen suicidal ideation and cause prolonged adverse events beyond acute effects, while paradoxically improving functional outcomes not captured by standard scales. Qualitative exploration of serious adverse events and participant accounts is needed to better understand psilocybin's varied outcomes.