Reframing “Treatment-Resistant” as “Difficult-To-Treat”

What do tertiary neurosyphilis and Freudian psychoanalysis have in common?

Each led psychiatry to write off common symptoms as simply “untreatable,” a verdict that said more about the paradigm’s limits than the prognosis.

Our cover stories this month provide a framework to facilitate the restructuring of our current habitual approach to casually and commonly define a patient’s disorder as treatment resistant, a term loaded with confusion and commonly limited to medication failure, and one that imbues hopelessness in the patient and frustration in the clinician. The authors of both cover articles, John Rush, MD, and Walter Paganin, MD, PhD, explore approaches to improve our characterization and, hence, inform our treatment planning, with the goal of better treatment outcomes.

Tertiary Neurosyphilis: A Cautionary Tale in “Treatment-Resistant” Diagnoses

Tertiary neurosyphilis, referred to as general paresis of the insane and dementia paralytica, was once one of the most common diagnoses of patients in psychiatric institutions in the United States and Europe.

An often referenced review article on syphilis in clinical psychiatry¹ reported that before antibiotics, general paresis was the diagnosis of 5% to 10% of all initial psychiatric admissions, and, in the 1920s, more than 20% of patients in psychiatric hospitals in the United States had tertiary syphilis.

It was the introduction of penicillin in the 1940s that transformed the usually fatal common and progressive neurosyphilis into a treatable and often preventable infection by Treponema pallidum. (Although mercury had been used to treat syphilis for centuries, it was toxic and poorly effective.) Thus, pre-penicillin neurosyphilis was erroneously deemed treatment resistant.

Freudian Psychoanalysis and the Myth of “Untreatable” Psychiatric Disorders

From the 1940s through the 1970s, Freudian psychoanalysis was the predominant model of psychiatric treatment taught and practiced in the United States. During this period, many biologically based and severe developmental trauma–based diagnoses were deemed untreatable by this psychoanalytic paradigm. Dementia praecox (schizophrenia), severe melancholia (severe major depressive disorder), mania (bipolar I disorder, manic), severe obsessional states (obsessive compulsive disorder), and borderline personality disorder (BPD) did not respond to psychoanalysis, with Freud concluding that individuals with these diagnoses could not establish the transference relationship he believed was necessary for psychoanalytic treatment.

As psychiatry matured as a medical specialty with the introduction of psychopharmacology, specialized types of psychotherapy, psychosocial supports, neuroimaging, and interventional treatments, Freudian psychoanalysis appropriately drifted into the historical archives. (For interested readers, a historical review by John G. Gunderson, MD,² considered the pioneer who identified borderline personality disorder as a distinct psychiatric syndrome, is a must-read. He narrates the transformation of BPD, which psychoanalysis defined as an untreatable neurosis, to a validated diagnosis with a range of evidence-based psychotherapies.)

Treatment-Resistance in Depression, Bipolar Disorder, and Schizophrenia: How We Define It Today

Any psychiatric diagnosis can be characterized as treatment resistant, but this term is most commonly used to describe a lack of an effective treatment response in major depressive disorder (MDD), bipolar disorder, and schizophrenia. Although there is no consensus definition of what constitutes treatment resistance in these disorders^3-6, the commonly used criteria include 2 prior failed appropriate medication trials of adequate dose and duration. This limited and insufficient definition has been reinforced by a complicit, agreed-upon usage among treatment providers, screening criteria for clinical trials, review by the FDA, and, of course, as a criterion required for a treatment to be authorized by the payer. It is not a stretch to ask why the label “treatment-resistant” carries no requirement to account for what other treatments were, or weren’t, attempted. For example, why are we not looking at evidence-based psychotherapies, medication adherence documentation, sleep hygiene education and monitoring, regular ongoing physical activity, minimizing substance use, a detailed review of medical and other psychiatric comorbidities, psychosocial stressors, early-life trauma, recent significant life changes and acute stressors, patient motivation, and secondary gain, to name a few?

Additionally, before the treatment-resistant label is enshrined in a patient’s medical record, a thorough repeat psychiatric assessment should be performed, as well as a re-review of any records from previous psychiatric treatment and, when indicated, a review (or order) of blood labs and neuroimaging. Despite the expert recommendation to document a therapeutic medication level before concluding a treatment has failed, especially in schizophrenia and bipolar disorder, it is rarely done in the United States.^7-9

In my 4-decade-long experience of consulting on treatment resistance in MDD, most of the medication trials were from the same class. In my opinion, this finding should preclude a diagnosis of treatment resistance until at least 1 additional medication trial from a very different class is completed, with the additional factors implemented as previously discussed.

Findings from a large episode-level retrospective study of patients with MDD shed light on this issue. The study used claims data from the IBM MarketScan Commercial and Medicare Supplement databases to evaluate the course of pharmacological treatment over time using up to 3 lines of therapy in the first 2 depressive episodes.¹⁰A total of 48,440 individuals met the inclusion criteria and began with the first line of pharmacotherapy, which was a selective serotonin reuptake inhibitor (SSRI) in 63% of participants. Those cases that did not respond were cross-titrated to any of a wide range of antidepressants, which could include augmentation with an FDA-approved atypical antipsychotic or bupropion. A total of 3317 of the original participants (6.8%) reached a third line of pharmacotherapy and were considered to have treatment-resistant depression (TRD). In the 20 most commonly observed pharmacotherapy sequence patterns in this treatment-resistant group, approximately 24% of participants had cycled through 3 different SSRIs for all 3 lines of pharmacotherapy. The other 19 treatment sequences were each used in less than 5% of individuals. The study was a retrospective, blinded analysis of data, so it is not known what the prescribers’ specialty mosaic included.

Measurement-Informed Care vs Measurement-Based Care: What the Evidence Shows

In our lead cover story, Rush reviewed the data supporting greater implementation of measurement-informed care (MIC), a recent nuanced modification of the well-established model known as measurement-based care (MBC), which he has practiced since his psychiatric residency.

Despite a plethora of solid evidence documenting the benefit of MBC/MIC, it remains greatly underutilized in psychiatry. Rush has authored and edited more than 10 books and more than 1000 articles covering a wide range of clinical topics, most notably major depressive disorder and MBC. Reflecting on his lifelong immersion in clinical and research psychiatry, Rush shared his insights into how we can improve patient outcomes via the routine use of evidence-based measurement tools.

Difficult-to-Treat Depression: How It Differs from Treatment-Resistant Depression

Our accompanying cover story is an intriguing commentary by Paganin, a clinical practitioner and researcher at the University of Rome Tor Vergata, Italy, whose primary area of interest is difficult-to-treat depression (DTD) and how it differs from TRD. Being unfamiliar with the term DTD, I did a deep dive into the literature, and boy, was I surprised.¹¹

DTD is a well-established descriptor of a depressive episode that has failed adequate antidepressant trials, yet the patient continues with significant clinical distress and functional impairment. Rather than continuing with medication trial after medication trial, a disease management approach is implemented alongside good pharmacotherapy, with the goal of using a range of interventions to reduce symptoms, optimize function, and improve quality of life. DTD expands the psychotherapeutic and social interventions early in treatment, rather than after multiple failed medication trials.¹²As serendipity would have it, Rush has been actively involved in the research on DTD as well.¹³

The Case for Retiring “Treatment Resistant”

It is heartening to know that a medical condition that is currently “untreatable” or “treatment resistant” exists on a timeline where history has consistently shown us they can transform in a positive direction as the drums of time beat on. We at Psychiatric Times are pleased to bring to you this month’s cover stories, along with our Depressive Disorders Special Report, to fuel your optimism as science and medicine march forward.

My opinion is that we should eliminate the term treatment resistant for all psychiatric disorders and replace it with difficult to treat. What do you think?

References

1. Hutto B. Syphilis in clinical psychiatry: a review. Psychosomatics. 2001;42(6):453-460.

2. Gunderson JG. Borderline personality disorder: ontogeny of a diagnosis. Am J Psychiatry. 2009;166(5):530-539.

3. McIntyre RS, Alsuwaidan M, Baune BT, et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023;22(3):394-412.

4. Menon V, Ganesh R, Deep R, et al. Clinical practice guidelines for the management of bipolar disorder: 2025 update. Indian J Psychiatry. 2026;68(1):8-43.

5. Nucifora FC, Woznica E, Lee BJ, et al. Treatment-resistant schizophrenia: clinical, biological, and therapeutic perspectives. Neurobiol Dis. 2019;131:104257.

6. Lim CS, Donovan AL, Vyas CM, et al. Treatment-resistant schizophrenia: evaluation and management. Prim Care Companion CNS Disord. 2024;26(4):23f03692.

7. Schoretsanitis G, Kane JM, Correll CU, et al. Blood levels to optimize antipsychotic treatment in clinical practice: a joint consensus statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie. J Clin Psychiatry. 2020;81(3):19cs13169.

8. McCutcheon R, Beck K, D’Ambrosio E, et al. Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia. Acta Psychiatr Scand. 2018;137(1):39-46.

9. Horvitz-Lennon M, Mattke S, Predmore Z, Howes OD. The role of antipsychotic plasma levels in the treatment of schizophrenia. Am J Psychiatry. 2017;174(5):421-426.

10. Wu B, Cai Q, Sheehan JJ, et al. An episode level evaluation of the treatment journey of patients with major depressive disorder and treatment-resistant depression. PLoS One. 2019;14(8):e0220763.

11. McAllister-Williams RH, Arango C, Blier P, et al. The identification, assessment and management of difficult-to-treat depression: an international consensus statement. J Affect Disord. 2020;267:264-282.

12. Paganin W. Treatment-resistant depression: time to rethink current definitions and clinical practice. Front Psychiatry. 2026;16:1733678.

13. Rush AJ, Sackeim HA, Conway CR, et al. Clinical research challenges posed by difficult-to-treat depression. Psychol Med. 2022;52(3):419-432.