During the past two decades, reference to “treatment resistance” (TR) has soared in psychiatric practice and literature, yet there is no consensus on the criteria for this term across diagnoses. Currently 20-60% of all psychiatric treatments end in failure or suboptimal outcomes, yet tertiary care centers find that in 3/4 of cases referred as TR, valid treatment options remain to be implemented. Incautious application of this pseudo diagnosis has become a harmful meme in psychiatry, misdirecting practitioners from better critical thinking and problem solving and leaving our patients demoralized, ill, and, often, hopeless.
The term TR originally referred to the quality of proposed treatments, but never diagnoses or patients. Disappointing responses, alongside successes, have been reported since the initiation of all interventions for mental illness: psychotherapeutic, symptomatic, occupational, somatic, and pharmacological. The term treatment resistant depression (TRD) first appeared in the literature in the 1970s to describe weak responses to some proposed antidepressant medications, but by the 1990s had become an entity unto itself, despite no consistent definition or clear criteria. In a recent expert consensus, 85% of practitioners admitted using the term TRD in practice, though 100% yearned for a standard definition.
Less than 1% of all psychiatric research currently addresses TR, though scholarly reference to it has surged 75% over the past two decades. Discussion of the concept is stymied by inconsistent definitions and criteria applied by individual authors and researchers to most psychiatric diagnoses. Assessment methods as well as the number, type, length, and quality of treatment attempts are not standardized for any diagnosis, including depression, schizophrenia, OCD, and PTSD. As a result, literature review finds many different individual explanations for treatment failure rather than identifying a valid diagnosis of TR.
There are myriad reasons for treatment failure (TF), and each situation is unlikely to share the same cause(s) as another. Iatrogenic alterations from therapies may contribute to TF, in vivo tachyphylaxis remains unclear, and declining response rates to subsequent pharmaceutical trials results in lower placebo response rates. The number of previous treatment trials is predictive of TF in some reviews but not in others. Data linking TF with personality disorders are weak or nonconfirmatory.
There is no association with TRD and augmentation or switching strategies. Similarly, there is no connection with specific drugs or molecules. Insufficiently examined lifestyle issues frequently sabotage clinical outcomes. There is some evidence that genetic and epigenetic factors play a role in TF when mislabeled as TRD or treatment resistant schizophrenia (and other forms of psychosis). Some genetic polymorphisms are linked to TF, and rare metabolic disorders will infrequently interfere with response to standard treatments. Ethnic and socioeconomic factors also play a role. In other words, heterogeneous biotypes respond to different mechanisms of action.
“Treatment resistance” is a chimeral term, a misconception resulting from reification — our belief that our conceptualizations always match reality. How has this unsupported idea become so entrenched in everyday psychiatric practice? Our brains work to limit complexity and uncertainty, while also applying the least cognitive effort to every problem-solving attempt. As a result, we rapidly pattern-match, often copying the opinions and approaches of others. The more practitioners use the term TR, the more others copy them with insufficient critical evaluation. Our minds proceed to diagnose quickly, shutting off the further exploration and reflection that is necessary to avoid TF and find individual solutions for each patient.
As a result, undiagnosed psychiatric and non-psychiatric comorbidities are often responsible for TF and suboptimal outcomes. We frequently fail to consider these, as we are automatically satisfied with our first diagnosis, correct or not, and too often fail to complete a broad and sufficient differential diagnosis. When we apply the unsanctioned term TR to a clinical situation, we feel we have found the answer. When we instead use the term TF, we realize that we have much work yet to do.
Exploring TF, we can then admit that our original model is flawed (as all are), reexamine our data, find important gaps, and generate new questions to answer and hypotheses to test. As clinicians, we acknowledge that at times we will have to consciously deconstruct and reassemble our initial impressions and conclusions, searching for bias and cognitive error. We must make this an iterative process, repeating it with each TF and suboptimal outcome until a patient receives satisfactory results.
We must also recall that hope is necessary for clinical recovery — for the patient and also for the clinician. When we use the term TR, we display harmful indecision rather than natural uncertainty. We are telling patients, as well as ourselves, that we are out of ideas. This often erodes their confidence in us and our therapeutic alliance with them, leaving many feeling hopeless — which is neither necessary nor therapeutic.
As 1/3 to 1/2 of contemporary psychiatric treatments are suboptimal, we must move beyond the misleading concept of TR, eschewing the term in favor of other, more helpful words. We can instead describe a case as “difficult to treat,” “under study,” or “pending remission,” indicating our intention to steadfastly proceed until satisfactory answers are found. The next time you hear the term TR, ask the speaker what they mean by it and where their remodeled differential now points. Refuse to accept TR as a valid or final assessment. Embrace TF, instead, as valuable information to be seriously considered while you continue to pursue a challenging clinical puzzle, solely to benefit your patient. To do anything else weakens our problem-solving skills and violates our responsibility to those in our care.
Dr. Putman, in Austin, TX, is the author of “Rational Psychopharmacology: A Book of Clinical Skills,” “Encountering Treatment Resistance: Solutions Through Reconceptualization,” and “Thinking Again: Reducing Cognitive Error in Psychiatric Practice.” He blogs at drpaulputman.com. Dr. Putman was a 2024–2025 Doximity Op-Med Fellow, and continues as a 2025–2026 Doximity Op-Med Fellow.
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