Treatment-Resistant Depression as a Dynamic Continuum: A Consensus Panel Report on Mechanism-Informed Pharmacologic Sequencing.

Treatment-resistant depression (TRD) affects a substantial proportion of patients with major depressive disorder and is associated with significant functional impairment, elevated suicide risk, and increased treatment complexity. In December 2025, a multidisciplinary expert consensus panel convened in Boston, Massachusetts, to address contemporary challenges in the identification and pharmacologic management of TRD. The panel concluded that TRD is best understood as a dynamic continuum reflecting the interaction between illness biology, patient complexity, and cumulative treatment history-not a categorical end point defined only by a fixed number of prior failures. Early identification of inadequate antidepressant response through measurement-based care, diagnostic reassessment, and active comorbidity management is essential to preventing entrenched resistance and functional decline. Pharmacologic sequencing should prioritize mechanistic diversity, with nonresponse prompting a mechanism switch and partial response prompting augmentation; as resistance arises, timely referral and consideration of therapies targeting glutamatergic signaling and potentially related neuroplasticity are warranted. Special populations-including patients with suicidality, comorbid anxiety or trauma, and unrecognized bipolarity-require faster escalation and closer monitoring. To support clinical implementation, the panel developed a 4-stage framework-spanning initial detection through high-acuity interventions-that operationalizes these recommendations across levels of care. These consensus recommendations are intended to help clinicians act earlier, sequence treatments more strategically, and match pharmacologic choices to the biology underlying each patient's resistance. J Clin Psychiatry 2026;87(3):htrdachi2508.