Treatment-resistant depression

Depression that has failed to remit despite adequate trials of multiple evidence-based treatments — most commonly defined as failure of two or more antidepressants at adequate dose and duration, often including augmentation strategies and psychotherapy. TRD defines the population in which invasive neuromodulation is considered.

Its heterogeneity is a major confound. Patients labeled 'TRD' differ widely in symptom profile, comorbidity, chronicity and the staging definition each study uses, so trials that pool clinically diverse patients under one anatomical target can dilute a real effect that exists only in a subgroup. This heterogeneity is a central argument for biomarker-based stratification — matching patient to circuit and target — rather than treating TRD as a single homogeneous disorder.