Treatment-Resistant Depression as a Dynamic Continuum

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https://www.psychiatrist.com/jcp/treatment-resistant-depression-dynamic-continuum-consensus-panel-report

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

Sep 23, 2026

EXCERPTS ONLY

Abstract

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.

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Rationale and Conceptual Framework

Major depressive disorder (MDD) remains one of the leading causes of disability worldwide, yet a substantial proportion of patients fail to achieve remission despite appropriate treatment. Across clinical trials and real-world settings, approximately one-third of individuals with MDD experience persistent symptoms following multiple antidepressant trials, a clinical scenario commonly referred to as treatment-resistant depression (TRD).1 Clinically, TRD is associated with greater symptom chronicity, functional impairment, and morbidity, while health care systems bear a disproportionate share of utilization and cost. In the United States alone, TRD accounts for a substantial share of the economic burden associated with MDD.1 Despite advances in pharmacotherapy, treatment for TRD continues to represent a major unmet clinical need.

Although TRD is widely recognized, its definition and clinical application remain inconsistent. In both clinical practice and research, TRD is most often operationalized as an inadequate response (ie, <50% improvement2) to at least 2 antidepressant trials of adequate dose and duration within the current depressive episode.3 While this definition offers pragmatic simplicity, it inadequately reflects the heterogeneity of depressive illness and the realities of real-world care and is more derived from the regulatory framework required for approval of new agents for TRD. It does not fully account for subtherapeutic dosing, insufficient duration, poor adherence, diagnostic uncertainty, or the influence of comorbid psychiatric and medical conditions.3 As a result, patients may be labeled as treatment resistant without a clear understanding of whether resistance reflects true biological nonresponsiveness or potentially modifiable clinical factors. Reflecting these limitations, an international consensus has argued for a shift in framing toward the term “difficult-to-treat depression,” defined as depression that continues to cause significant burden despite usual treatment efforts, which emphasizes ongoing, individualized management of persistent illness rather than a binary determination of resistance.4 The panel recognized the value of this perspective but retained the term TRD for consistency with current regulatory and clinical usage.

Importantly, TRD should not be solely conceptualized as a categorical state that emerges abruptly after a fixed number of treatment failures. There is the common belief that TRD is the same as “treatment refractory,” but “treatment resistant” can be identified as early as after 2 lines of treatment. Similarly, the idea that TRD is caused by numerous treatment failures is not compatible with our current biological understanding of depression. Rather, TRD represents a continuum of increasing treatment complexity that evolves over time. Biological vulnerability, psychological processes, environmental stressors, and treatment-related factors interact dynamically, often through epigenetic mechanisms, shaping both illness trajectory and treatment responsiveness.5 From this perspective, resistance may develop gradually as ineffective or poorly matched interventions accumulate, and opportunities for timely reassessment and mechanistic change are missed.

This continuum-based view has important implications for clinical decision-making. Early symptom improvement is a robust predictor of long-term outcome, yet in routine practice, ineffective treatments are frequently continued without structured reassessment.6 Early improvement, often defined as approximately 20% symptom reduction within 2 weeks of initiating therapy and 25%–50% reduction in symptoms by 4–6 weeks on validated measures such as the Patient Health Questionnaire-9 (PHQ-9) and the 5-item World Health Organization Well-Being Index (WHO-5), has been shown to predict subsequent remission.7,8 The absence of early measurement-based evaluation contributes to treatment inertia, delayed escalation, and progressive functional decline.9–11

Within this context, 2 complementary approaches to defining TRD are useful. A practical definition emphasizes early, measurement-based thresholds to guide clinical action. Failure to meet early response benchmarks should prompt reconsideration of treatment strategy rather than prolonged continuation of ineffective therapy. However, reliance on response thresholds alone risks oversimplification when applied without adequate diagnostic clarity or contextual assessment.

Accordingly, a broader conceptual framework is required. Depression is increasingly understood as arising from a complex adaptive system in which biological, psychological, and environmental forces interact dynamically, often through epigenetic mechanisms.5,12 Within this framework, TRD is not viewed as a fixed clinical trait or an absolute biological barrier. Rather, it represents a state of therapeutic nonresponsiveness within a complex system, signaling that the current intervention has failed to engage the specific mechanisms required to shift the system toward recovery. Consequently, the “resistance” observed is relative to the intervention’s mechanism of action, necessitating a timely transition to alternative therapeutic targets.

Emerging evidence suggests that inflammatory markers, neurotrophic factors, and other circulating biomarkers may differentiate subtypes of depression.13–15 In addition, pharmacogenomic variability—including pharmacokinetic genotypes (eg, CYP2D6) affecting drug metabolism and systemic exposure and pharmacodynamic genotypes (eg, SLC6A4) affecting target engagement—can influence antidepressant response. These factors often contribute to apparent resistance, where a patient’s lack of response or poor tolerability reflects a pharmacologic mismatch rather than an inherent inability to achieve remission.16,17

Despite the availability of clinical practice guidelines, uncertainty persists regarding optimal timing of reassessment, criteria for escalation, selection of mechanistically distinct therapies, and referral pathways for patients with evolving or established TRD. Guidelines are effective at establishing whether an intervention is supported by evidence but frequently provide limited operational guidance for implementation across heterogeneous patient populations or complex real-world settings.18,19 As a result, clinicians rely heavily on individual judgment and local practice patterns, leading to substantial variations in care.

To address these gaps, a multidisciplinary expert consensus panel was convened to examine contemporary challenges in the identification and pharmacologic management of TRD. The objectives of the panel were to develop a clinically actionable conceptual framework, define practical indicators for early identification and escalation, and achieve consensus on evidence-based pharmacologic sequencing informed by underlying mechanisms and real-world constraints. Through facilitated discussion and review of publicly available evidence, the panel proposed an approach emphasizing early reassessment, routine use of measurement-based care to guide decisions, and avoidance of treatment inertia through timely switching or augmentation.

Currently, intranasal esketamine and olanzapine/fluoxetine combination are the only pharmacologic agents with specific regulatory indications for TRD. Esketamine is indicated for use in the United States in adults with TRD as monotherapy or in conjunction with an oral antidepressant. Patients in the short-term TRD studies included those who had not responded adequately to at least 2 different antidepressants of adequate dose and duration in the current depressive episode. In clinical practice, atypical antipsychotics are frequently utilized to augment antidepressant outcomes in partial responders, an approach recommended as an augmentation option across contemporary treatment guidelines,20–22 while off-label ketamine use is a strategy that may be used in more refractory cases.23 The framework and recommendations presented in this Academic Highlights are intended to support timely, mechanism-informed decision-making across levels of care and reduce unwarranted variation in the treatment of MDD and TRD.

Methods

In December 2025, a multidisciplinary panel of experts in psychiatry, psychopharmacology, and the clinical management of TRD convened for an in-person consensus meeting in Boston, Massachusetts. The purpose of the meeting was to develop a clinically oriented framework for the assessment and staged management of TRD, with emphasis on treatment sequencing, mechanistic considerations, and real-world implementation.

The meeting was conducted using a structured agenda with facilitated discussion. To maintain a focused and clinically actionable scope, discussion was limited to the pharmacologic management of TRD, with nonpharmacologic interventions addressed only when necessary for contextual completeness. Panelists reviewed and discussed publicly available evidence from clinical trials, regulatory guidance, and relevant clinical practice literature and shared experiential insights from routine clinical care. Consensus was achieved through iterative discussion, with areas of agreement reflected in the recommendations presented in this article.

This article summarizes the consensus perspectives generated during the panel meeting and is intended to support clinicians in applying evidence-based and patient-centered approaches to the management of TRD across care settings.

AnchorEarly Identification, Escalation, and Referral in MDD and TRD
Early identification of inadequate antidepressant response is a critical determinant of long-term outcomes in MDD. Multiple analyses have demonstrated that early symptom improvement (within 2 weeks) is strongly associated with subsequent remission, while the absence of early improvement predicts poor response and chronicity.6,24 Despite this evidence, treatment inertia remains common in both primary care and psychiatric practice, with ineffective therapies often continued for extended periods without structured reassessment.

Measurement-based care provides a practical framework for identifying evolving evidence of treatment resistance. Validated tools such as the PHQ-9, WHO-5, Beck Depression Inventory, 7-item Generalized Anxiety Disorder, Insomnia Severity Index, Snaith-Hamilton Pleasure Scale, Clinician Global Impression-Improvement scale, and Patient Global Impression-Improvement scale allow for measurable patient-and clinician-rated outcome metrics of symptom burden, functional impairment, and overall well-being.7,8 Regardless of the measure utilized, the panel reached consensus that objective improvement of at least 20% within 2 weeks of initiating therapy and at least 50% within 4–6 weeks has consistently been associated with a higher likelihood of remission, which is highly consistent with the literature.6,9,24 These thresholds align with current treatment guidelines: The Canadian Network for Mood and Anxiety Treatments (CANMAT) defines early improvement as a 20% or greater symptom reduction within 2–4 weeks and response as a 50% or greater reduction,20 and the Department of Veterans Affairs and the Department of Defense (VA/DoD) and National Institute for Health and Care Excellence (NICE) guidelines likewise treat a 50% or greater improvement as the threshold for response over a 4-to 6-week trial.21,22 Failure to achieve these thresholds should prompt timely modification of treatment rather than prolonged continuation of the same strategy.10,11

The panel agreed that escalation decisions should be guided not only by symptom change but also by ensuring adequate dosing and reassessment of diagnosis, adherence, tolerability, comorbidities, and prior treatment trials. Apparent nonresponse may reflect pseudo-resistance driven by misdiagnosis, including unrecognized bipolar spectrum illness, trauma-related disorders, substance use, or untreated medical contributors such as sleep apnea, chronic pain, thyroid disease, or cardiometabolic conditions.3 In addition, poor adherence and treatment discontinuation related to medication tolerability, including burdensome adverse effects or cumulative side effect load, are common and often underrecognized contributors to apparent treatment failure.25–27 Addressing these factors is essential before concluding that depression is truly treatment resistant.

The panel noted that when early improvement is not observed at a known therapeutic dose, treatment escalation generally involves either switching or augmentation. Pharmacogenomic factors, such as ultrarapid metabolizer status, can reduce drug exposure and may, in specific patients, warrant dose adjustment guided by therapeutic drug monitoring or selection of an alternative agent.28 Early response, noted as ≥20% reduction in symptom severity within 2 weeks, has been shown to predict stable response and remission with high sensitivity, whereas its absence is a strong predictor of subsequent treatment failure. Nonresponse, noted subjectively or based upon outcome metrics as <25% improvement in 4–6 weeks,2 often leads clinicians to consider an agent with a different mechanism of action, such as switching from an selective serotonin reuptake inhibitor (SSRI) to a therapy targeting a different monoaminergic pathway or a glutamatergic pathway. Partial response, noted as >20% symptom reduction in 2 weeks but between 25% and 50% in 4–6 weeks,2,24 by contrast, may be more amenable to augmentation strategies, including the addition of evidence-based pharmacologic agents or intensified psychological support. Measurement-based care supports this distinction by allowing clinicians to differentiate between no response and partial response early in the treatment course.29

Further, the panel noted that referral decisions represent a critical inflection point in the management of MDD and TRD. A common pragmatic threshold for referral to specialty care is failure of 2 adequate antidepressant trials. However, rigid adherence to numerical thresholds may delay appropriate escalation in clinically complex cases. Diagnostic uncertainty, persistent functional impairment, intolerable adverse effects, significant comorbidity burden, or limited treatment options in primary care settings may justify earlier referral to psychiatric specialists.30,31 Suicidality represents an independent accelerator for escalation and referral. Patients with acute or persistent suicidal ideation require expedited evaluation and may benefit from higher-acuity care settings or advanced interventions. In such cases, the goal shifts from incremental symptom improvement to risk reduction and rapid stabilization, often necessitating specialty infrastructure and close monitoring.32,33

Populations and Clinical Complexity

Suicidality represents the most urgent modifier of treatment strategy. Patients with acute or persistent suicidal ideation require expedited evaluation, closer monitoring, and, when appropriate, rapid escalation to higher-acuity or specialty care. In these cases, the primary objective shifts from incremental symptom improvement to immediate risk reduction and stabilization, often necessitating access to advanced or supervised pharmacologic interventions.

The panel noted that comorbid anxiety disorders, trauma-related conditions, and substance use disorders frequently complicate treatment response in MDD.

These comorbidities may attenuate antidepressant efficacy, increase the likelihood of adverse effects, or obscure early signals of response. When childhood trauma is suspected or disclosed, use of structured screening tools such as the Adverse Childhood Experiences scale may be informative.39 Patients with prominent anxiety or trauma histories may benefit from earlier mechanistic pivots and more frequent measurement-based monitoring, rather than prolonged trials of incremental monoaminergic adjustments.

Bipolar spectrum illness remains a critical consideration in patients with poor or inconsistent antidepressant response. Unrecognized bipolarity may manifest as apparent treatment resistance or antidepressant intolerance. Careful assessment of mood history, family history, and treatment-emergent mood instability is essential before escalating antidepressant therapy.

Medical comorbidities, including chronic pain, sleep disorders, cardiometabolic disease, and neurodegenerative conditions, can meaningfully influence both symptom presentation and treatment selection. In older adults, polypharmacy, altered pharmacokinetics, and heightened sensitivity to adverse effects necessitate a greater emphasis on tolerability and safety when sequencing therapies. Sex-specific factors also merit consideration, as emerging evidence suggests that women may be at higher risk for developing TRD and may experience differential treatment responses.