Treatment-resistant depression definitions may overlook social causes
Clinical definitions of treatment-resistant depression, centered on failed drug trials, are being critiqued for not aligning with depression's diverse social and psychological origins, potentially biasing care toward biological treatments.
Treatment-resistant depression is commonly defined by the failure of two adequate antidepressant trials, but definitions vary widely and lack alignment with depression’s diverse causes. Regulatory definitions from the US Food and Drug Administration and the European Medicines Agency anchor to this two-drug failure model. In the past two decades, this framework has dominated, but it has limited alignment with the etiologic diversity within major depressive disorder. As one analysis noted, both major regulatory bodies have adopted this most widely used definition. The concept suggests a condition where biology is the primary driver.
The disease model of depression and its consequences
Viewing major depressive disorder as a single disease biases treatment toward pharmacological and neurostimulatory approaches. This may obscure primary social or psychological drivers of antidepressant nonresponse. The base condition is commonly viewed as an entity, but it is no more a homogeneous entity than 'major breathlessness'. This entity status risks inviting singular, linear management models for treatment-resistant depression. It contrasts with a cancer model, where differing cancers invite differing treatment sequences. The common positioning of MDD as a 'disease' leads to TRD management models that weight physical treatments like switching antidepressants, augmentation drugs, electroconvulsive therapy, other neurostimulatory strategies, and ketamine.
Real-world cases where biology is not the driver
Cases of depression rooted in life circumstances can meet TRD criteria despite lacking a primary biological basis. A mother with persistent depression due to a physically abusive husband, who controls the family finances, meets criteria for MDD. A lawyer with a perfectionist personality, shamed publicly by a superior into a prolonged depressive state, also meets the criteria. If their doctors prescribe three antidepressants of different classes at adequate doses for many weeks with no response, these scenarios meet the common definitional criteria for TRD. Antidepressant medication is unlikely to be therapeutic in these situations.
Psychotherapy’s role and limitations in TRD
Psychotherapeutic interventions may be a preferred treatment option over pharmacotherapy for some patients. They may assist with residual symptoms and comorbidities, synergize with medications, and be salient for those with persistent depression and trauma. However, data supporting them as standalone interventions in TRD are limited. In operational management models, psychotherapeutic interventions are generally either not included or positioned as adjunctive. This reflects the historical weighting toward biological treatments established when the TRD concept was introduced.
Refining the approach for different depressions
If MDD is a nonspecific diagnosis capturing a heterogeneous set of conditions, then all have the potential to be resistant to treatment. This resistance may reflect a paradigm failure in choosing management strategies. The evidence for specific treatments varies greatly by depressive subtype.
For melancholia, next-stage recommendations after a broad-spectrum antidepressant include lithium augmentation or several second-generation antipsychotics. Alternatives weighting dopaminergic transmission are also offered. These include olanzapine augmentation for only one to two weeks, reflecting a 'jump leads to the battery' model, or augmenting with a stimulant drug like methylphenidate. Other options for TRD in general include combining certain antidepressants, using other dopaminergic antipsychotic drugs, neurostimulatory treatments, and ketamine.
Primary care providers prescribe 79% of all antidepressant medications in the United States. A new initiative aims to support them. Project ECHO at Penn State College of Medicine and the National Network of Depression Centers are launching a no-cost, virtual measurement-based care training series. The program, titled 'What to Do When My Depressed Patient is Not Improving: Measurement-Based Care,' runs monthly on Tuesdays from 8 to 9 a.m. ET, starting Oct. 20. Registration is required. The series is open to primary care providers, nurses, physician assistants, and clinical staff. Participants will use an 'All Teach, All Learn' model to talk directly with experts like Professor Mark Williams of the Mayo Clinic and Dr. Errol Aksu of Penn State Health. During sessions, attendees will learn how to diagnose treatment-resistant depression, manage medications, handle risks, address hidden issues, and integrate therapies. No-cost Continuing Medical Education credits are available. The no-cost virtual measurement-based care training series for primary care providers launches monthly on Tuesdays from 8 to 9 a.m. ET, starting Oct. 20, with registration required and CME credits available.
