Treatment-Resistant Depression as a Heterogeneous Clinical Syndrome: A Personalized Medicine Framework for Diagnostic Reassessment, Suicide Risk, and Mechanism-Based Treatment

Background: Treatment-resistant depression (TRD) is an operational category based on inadequate outcome after adequate antidepressant treatment. The same label may encompass insufficient treatment exposure, an incorrect primary diagnosis, clinically important comorbidity, or depressive illnesses with different maintaining mechanisms. This heterogeneity limits the clinical meaning of treatment history alone and complicates individualized care. Objective: To integrate evidence on diagnostic reassessment, suicide risk, neurobiology, psychological and functional factors, and treatment, and to define a clinically testable personalized medicine framework for TRD. Methods: Targeted PubMed/MEDLINE searches were conducted from database inception through 31 July 2026 and supplemented by reference-list searching. Two authors independently assessed publications for relevance, and disagreements were resolved by discussion and consensus. Ninety-six sources were included and synthesized narratively. Results: Inadequate exposure or adherence can produce pseudo-resistance, whereas bipolar spectrum illness, neurodevelopmental or trauma-related conditions, personality pathology, sleep or substance-related disorders, and medical disease may represent alternative diagnoses, comorbidities, or modifiers of treatment course. Glutamatergic signaling, impaired plasticity, stress-system dysregulation, inflammation, circadian disturbance, metabolism, and neural circuitry contribute to heterogeneity at the group level but do not define validated individual subtypes. Established pharmacological, psychological, and neuromodulatory interventions should be selected according to diagnosis, severity, urgency, previous response, comorbidity, functional impairment, safety, feasibility, and patient preference. Conclusions: TRD is an operational treatment-history category, not a unitary disease. A personalized medicine approach begins with confirmation of major depressive disorder, adequate treatment exposure and adherence, followed by parallel treatment of depression and clinically relevant comorbidity. Biomarkers should guide allocation only when they provide prospectively validated predictive value beyond high-quality clinical and functional assessment.