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SAN FRANCISCO — A novel self-report questionnaire may help identify patients who are at risk for difficult-to-treat depression before they meet the criteria for treatment-resistant depression (TRD).

Building on earlier research, investigators assessed whether the Difficult-to-Treat Depression Questionnaire (DTDQ) could predict outcomes in patients with major depressive disorder (MDD) who had not responded to multiple antidepressant treatments.

In this cohort of patients treated in a partial hospital program, the DTDQ predicted poorer outcomes at discharge, including greater depressive and nondepressive symptoms, greater functional impairment, and lower quality of life.

“The way I can envision [the DTDQ] mattering clinically is you can begin to think more and earlier about including psychotherapeutic approaches along with pharmacological approaches and focusing more on helping an individual to improve the quality of their life, not just eliminate their symptoms…. And symptom improvement is more likely to follow functional improvement rather than precede it,” study investigator Mark Zimmerman, MD, chief of psychiatry and behavioral health at South County Psychiatry in North Kingstown, Rhode Island, and director of the Rhode Island Methods to Improve Diagnostic Assessment and Services project, told Medscape Medical News.

The study was presented on May 18 at the American Psychiatric Association (APA) 2026 Annual Meeting.

A Stigmatizing Diagnosis

An estimated one third of patients with MDD are diagnosed with TRD, which is defined as failure to respond to two or more treatments. However, some experts believe this diagnosis is stigmatizing and have called for TRD to be reconceptualized as difficult-to-treat depression.

“I have never, in my 30-plus years of practice, said to a patient that they have [TRD]. I just intuitively viewed that as basically telling a person, ‘You’re never getting better,’” Zimmerman said at a press briefing.

The DTDQ is the first self-report scale to assess difficult-to-treat depression and captures a variety of clinical and psychosocial factors beyond the number of failed treatments.

More than two decades ago, the term difficult-to-treat depression was introduced as a conceptual shift away from TRD, offering a less stigmatizing diagnosis and a different approach to treatment.

Rather than focusing primarily on symptom remission, the difficult-to-treat depression model emphasizes disease management, with the goal of helping patients improve their functioning and quality of life.

Research shows that patients with depression care more about everyday functional improvement, whereas clinicians care more about a reduction in symptoms, Zimmerman highlighted. “There’s this disconnect between what clinicians think is most important and what patients think is most important,” Zimmerman said.

A 2020 consensus on difficult-to-treat depression emphasized the need for a comprehensive patient assessment that includes physical, psychological, and psychosocial factors.

Such evaluations can be time-consuming and expensive, so Zimmerman set out to develop a self-report questionnaire that captures factors associated with poor outcomes based on the broader depression literature.

He developed the DTDQ, which asks patients to rank 39 items on a 5-point scale. These items assess the severity and duration of depression, anxiety, anger, recent life stress, coping ability, childhood trauma, social support, physical health, pain, the efficacy of prior medication and psychotherapy, and expectations of benefit from current treatment.

Zimmerman highlighted the perceived deservingness of recovery as a key item on the DTDQ.

“About one sixth of patients, while they want to get better, do not assert that they think they deserve to get better. And not surprisingly, it’s much more difficult to engage someone in treatment and help them get better if they don’t think they deserve to get better,” he said.

Earlier Path to Care?

In a 2023 study evaluating the reliability and validity of the DTDQ, Zimmerman and co-investigator Daniel Mackin, PhD, assessed patients with MDD at admission and discharge from a partial hospital program. The outcome measure was the Remission from Depression Questionnaire (RDQ), which assesses depressive symptoms, quality of life, and functional and coping ability.

Among 550 patients, higher DTDQ scores were associated with more depressive and nondepressive symptoms, poorer coping, greater functional impairment, and lower quality of life at discharge.

DTDQ scores remained significantly correlated with outcomes after controlling for the number of failed trials. However, when they controlled for DTDQ scores, the number of failed trials was no longer a reliable predictor of outcomes, suggesting that the DTDQ assesses factors relevant to recovery beyond treatment history alone.

The next step was to determine whether the DTDQ could predict treatment outcomes in patients without multiple treatment failures. In Zimmerman’s latest study, 211 patients with MDD completed the DTDQ and RDQ at baseline and discharge.

Correlations between DTDQ and RDQ scores were assessed, and group comparisons were conducted using the established DTDQ cutoff score of 88 identified in the previous study. Analysis of covariance models was used to test outcome differences, while controlling for baseline scores.

Among patients who were not treatment-resistant, the DTDQ successfully predicted treatment outcomes at discharge, including greater total RDQ scores (r = 0.39, P < .001), depressive symptoms (r = 0.40, P < .001), nondepressive symptoms (r = 0.46, P < .001), functional impairment (r = 0.30, P < .001), and quality of life (r = 0.28, P < .001).

“These findings suggest that patients with difficult-to-treat depression may no longer be subject to repeated medication trials in order to receive the specialized care they need,” Zimmerman said in a news release.

“The DTDQ expands on our traditional understanding of [TRD], incorporating psychosocial and illness-related risk factors into the existing framework and opening the door to a new perception of treating and coping with depression.”

Limitations of the research included the fact that the sample was from a single-site partial hospital program, and patient outcomes were self-rated.

A Compassionate Approach

One outside expert said the findings add to growing efforts to better identify patients at risk for poor depression outcomes.

Howard Liu, MD, MBA, praised the DTDQ as a thoughtful and innovative tool for depression care.

“I think that having heard how this was derived from decades of practice, from a compassionate approach with the dignity of the patient in mind, it’s much easier to say, ‘Well, this will actually be helpful.’ It’s not just for the clinician, it’s for the patient, right? So, you do it together, almost as a dialogue starter,” Liu, chair of the Department of Psychiatry at the University of Nebraska Medical Center in Omaha, Nebraska, told Medscape Medical News.

Liu is considering implementing the tool in his own practice as well as reflecting on the use of language in depression treatment.

“I am going to talk to my clinicians about whether we should rename our [TRD] clinics because of the stigma that we are unconsciously reinforcing,” he said.

Liu added that he hopes the tool will be more widely used so that it can be refined over time and applied in different communities.

Liu and Zimmerman declared having no relevant disclosures.