The Journal of Clinical Psychiatry
Academic Highlights

Clinical Pearls

Treatment-resistant depression as a dynamic continuum: a consensus panel report on mechanism-informed pharmacologic sequencing

Anita H. Clayton, MD (Chair); Michael Asbach, DMSc, PA-C, Psych-CAQ; Patricia Cabrera, MD; Cristina Cusin, MD; Jay Fawver, MD; Jordan F. Karp, MD; Laura Leahy, DrNP, APRN, FAANP, FAAN

What is treatment-resistant depression (TRD)?

TRD represents a continuum of increasing treatment complexity that evolves over time.

Most often operationalized as

<50% improvement after at least 2 antidepressant trials of adequate dose and duration

Consensus panel view

Does not simply reflect failure of 2 adequate antidepressant trials
Resistance may develop gradually as ineffective or poorly matched interventions accumulate

How does TRD develop?

Biological vulnerability, psychological processes, environmental stressors, and treatment-related factors interact dynamically, often through epigenetic mechanisms, and shape both illness trajectory and treatment responsiveness.

Genetics, epigenetics, and environment feed into a network of interacting mechanisms — monoamine, GABA, and glutamate dysregulation, endogenous neuroactive steroids, HPA axis hyperactivity, reduced neuroplasticity, inflammatory mechanisms, and neural network dysfunction — that together contribute to major depressive episodes.

The biological underpinnings of major depressive disorder (MDD) and TRD extend well beyond monoaminergic dysfunction.

Adapted from publication Figure 1 (originally Clayton and Deligiannidis, 2023; with permission).

How soon can I tell the antidepressant isn’t working?

Early recognition of inadequate antidepressant response should guide timely treatment modification.

2 weeks

At least 20% symptom reduction

4–6 weeks

25% to ≤50% symptom reduction

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.

Before I call this TRD, what might I be missing?

Adequacy of treatment requires diagnostic clarity and comorbidity assessment.

Adequate trial

Diagnostic clarityTherapeutic dosingAppropriate durationConfirmed adherenceAcceptable medication tolerability

Pseudoresistance

Misdiagnosis (eg, bipolarity)Trauma exposureAnxiety disordersMedical contributorsSubstance misuse

Clinical Pearls · Treatment-resistant depression1 / 2

What to do when my patient doesn’t respond adequately?

Mechanistic diversity should guide pharmacologic sequencing.

Nonresponse (<25% improvement) should prompt a mechanism switch.
Partial response (25%–50% improvement) should prompt augmentation.
When multiple mechanisms fail, consider therapies that target glutamate-GABA dysregulation or other non-monoaminergic downstream pathways linked to synaptic plasticity.

How should I sequence treatment?

Pharmacologic sequencing should be understood as a framework for clinical risk stratification rather than a rigid, linear algorithm.

The pursuit of remission and functional recovery

Stage 1

Detection and initial treatment

Confirm diagnosis of MDD
Assess comorbidities and family history of diagnosis and treatment
Initiate 1st line therapy based on patient assessment:
SSRI
SNRI
Atypical antidepressants^a
Begin measurement-based care

Stage 2A

Nonresponse to treatment
Switch treatment

Minimal or no early improvement
Reassess diagnosis, adherence, tolerability
Switch to a mechanistically alternative therapy^b
Avoid repeated within-class cycling

Stage 2B

Partial response to treatment
Augment treatment

Partial but insufficient improvement
Add complementary mechanism^c
Balance efficacy, tolerability, patient priorities
Continue measurement-based monitoring

Stage 3

Specialty referral and advanced evaluation

Diagnostic uncertainty
Persistent functional impairment
Comorbidity burden or intolerance
Limited response despite adequate trials
Pharmacogenomic testing
FDA-approved TRD therapies

Stage 4

High-acuity/advanced interventions

Mechanistically distinct therapies^d
Neuromodulation
Expedited pathways for suicidality

^aAtypical antidepressants: bupropion, gepirone ER, mirtazapine, trazodone, vilazodone, vortioxetine. ^bMechanistically alternative therapies: atypical antidepressants, dextromethorphan-bupropion. ^cAntipsychotics with FDA approval as augmentation strategies in MDD: aripiprazole, brexpiprazole, cariprazine, lumateperone, quetiapine ER. ^dMechanistically distinct therapies: monoamine oxidase inhibitors, tricyclic antidepressants, lithium, triiodothyronine. Recreated from publication Figure 2, without its consensus statement boxes. ER = extended release; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor.

When should I refer to a specialist?

Referral and advanced pharmacologic interventions should be triggered by complexity, not just the number of failures.

Referral does not mean starting advanced treatment right away. It makes sure the right expertise and resources are in place as complexity grows.

Diagnostic uncertaintyComorbidity burdenFunctional collapseAcute risk

Suicidality represents an independent accelerator for escalation and referral.

The 4 consensus statements

Early recognition of inadequate antidepressant response should guide timely treatment modification.

Adequacy of treatment requires diagnostic clarity and comorbidity assessment.

Mechanistic diversity should guide pharmacologic sequencing.

Referral and advanced pharmacologic interventions should be triggered by complexity, not just the number of failures.

Based on

Clayton AH, Asbach M, Cabrera P, et al. J Clin Psychiatry. 2026;87(3):JCP.htrdachi2508. Published online September 4, 2026. doi.org/10.4088/JCP.htrdachi2508

Sponsor

The panel meeting was funded by Janssen Scientific Affairs, LLC, who also funded article processing charges, medical writing, editorial, and other assistance. Dr Cabrera is employed by Johnson & Johnson. The opinions expressed are those of the faculty. Faculty disclosures appear in the full article. This summary does not replace prescribing information.