Pharmacological Strategies for Treatment-Resistant Depression: Integrating Novel and Traditional Approaches with Psychopathological Insights

Background

Treatment-resistant depression (TRD), commonly defined as the failure to achieve adequate response after at least two appropriate antidepressant trials, represents a critical clinical condition in which standard diagnostic categories and stepwise treatment algorithms repeatedly fail; this operational definition itself exposes the limits of uniform models of depression, revealing it as an intrinsically heterogeneous condition composed of distinct depressive configurations rather than a single clinical entity.

Objectives

To propose an integrated framework for TRD that combines classical psychopathology, contemporary neurobiological domains, and established as well as emerging therapeutic strategies, in order to improve treatment matching in resistant cases.

Methods

Narrative and critical synthesis of European phenomenological psychopathology, dimensional neurobiological models, and clinical evidence on traditional, rapid-acting, and experimental treatments for TRD, interpreted through a domain-based approach.

Results

TRD emerges as the variable predominance of distinct symptom domains (e.g., anhedonic, anxious–arousal, cognitive, circadian, inflammatory-like), each associated with specific patterns of treatment response. Apparent resistance often reflects a mismatch between depressive form and therapeutic target, while a subset of patients may show genuine refractoriness. When aligned with the dominant domain, interventions such as ketamine and esketamine, dextromethorphan–bupropion, neuromodulation techniques (TMS, ECT), and emerging plasticity-oriented strategies—including psychedelic compounds and non-hallucinogenic psychoplastogens—acquire clearer clinical meaning.

Conclusions

TRD should be conceptualized as a qualitative configuration rather than a quantitative failure. Integrating psychopathological insight with domain-based neurobiology supports a personalized use of traditional treatments, rapid-acting glutamatergic agents, multimodal interventions, and experimental plasticity-enhancing therapies, offering a coherent framework for managing resistant depression.