Refining the Diagnosis When MDD Treatment Falls Short

When a patient does not respond to treatment for major depressive disorder (MDD), how can clinicians determine whether it’s an issue of an ineffective medication regimen or an incorrect diagnosis?

In this video filmed at Psych Congress 2026, Kristian Dambrino, DNP, PMHNP-BC, Clinical Editor, Psych Congress Journal, offers a framework for pinpointing when antidepressant nonresponse in MDD may be a byproduct of misdiagnosis. Dambrino first provides an overview of key clinical and patient features that may warrant further evaluation for a different mood disorder. She also explores how leveraging measurement-based care can help clinicians track medication response and identify treatment trends, providing valuable data to inform whether an MDD diagnosis should be reconsidered.

• Lack of improvement with antidepressant treatment for MDD should prompt diagnostic reassessment, including consideration of bipolar disorder (BD) and whether another condition may better explain the presentation.
• Anxious distress, periods of hypersomnia and insomnia, irritability, and family history may warrant further evaluation for BD when patients diagnosed with MDD do not respond to initial treatment as expected.
• Longitudinal use of measurement-based care, including screeners like the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) can help track symptoms and treatment response.

Kristian Dambrino, DNP, PMHNP-BC: Hey, I’m Kristian Dambrino and I’m a psychiatric nurse practitioner based in Nashville, Tennessee. I’m on faculty at Belmont University College of Nursing.

Psych Congress Network: When a patient with MDD does not improve as expected with an antidepressant, what clinical features should prompt clinicians to reconsider or refine the diagnosis?

Dambrino: If someone is not responding to an oral antidepressant and they’re diagnosed with major depressive disorder, we want to think about ruling out bipolar disorder. The anxious distress specifier is present in both MDD and BD, and that’s what makes it so difficult to differentiate those. 

We want to assess for sleep. Have there been periods of hypersomnia and insomnia, not just insomnia? And also [for] irritability. Sometimes those patients can come into our office with a very irritable presentation.

We also always want to assess family history. This should be the first thing that we’re asking about. That is a clue to rule out whether or not there may be BD. We know that there’s high heritability with dizygotic twins, with first-degree relatives, and we want to think about that when we have those patients with MDD who are presenting with anxious distress in the absence of generalized anxiety disorder (GAD). 

One of the ways we can also rule that out is to screen with the GAD-7, Mood Disorder Questionnaire (MDQ), which is the screening instrument for bipolar disorder, and, yes, we can use the PHQ-9, but the PHQ-9 is not going to be particularly sensitive at all for diagnosing bipolar disorder.

PCN: How should clinicians reassess the treatment plan when MDD symptoms continue to worsen despite multiple antidepressant trials?

Dambrino: If patients are reporting worsening depression in spite of multiple antidepressant trials, we absolutely need to be thinking about ruling out not just BD, but is the diagnosis correct at all? Are we looking at something completely different? Is it attention-deficit/hyperactivity disorder (ADHD)? Is it something that’s in a completely different domain? That is a very big indication that we may be on the wrong track. 

Again, I keep talking and we talk a lot at Psych Congress about measurement-based care. I think it’s something like 5% of clinicians are using measurement-based care at every visit. Using measurement-based tools—the PHQ9, the GAD7—is important to do over time so that we can look at trends. 

This is also helpful for patients. Sometimes our patients will say things like, “I feel like you’re just throwing spaghetti up against the wall with medications.” There is a science and there is an evidence base that we’re prescribing from, and so measurement-based care helps with that. 

We want to be revisiting the diagnosis if we see that. With antidepressants specifically, low-to-medium doses typically–we can’t generalize, we always know that every person can be different in their response– but we’re no longer thinking, “Let’s just max out the dose of this antidepressant to get the best result.” That’s not true for most of our patients and we know that in the literature. Those medium-to-low doses for treating depressive episodes are typically going to be most efficacious. If we have that in multiple trials and the patient’s still not getting better, we need to revisit the diagnosis.

Kristian Dambrino, DNP, PMHNP-BC, is a board-certified psychiatric nurse practitioner and the founder of Dambrino Wellness, a mental health clinic in Nashville, Tennessee. She holds a Master of Science in Nursing from Vanderbilt University and a Doctor of Nursing Practice from Belmont University.

A Fulbright Scholar, she is conducting research in Indonesia and India on reducing mental health stigma through nursing capacity building, and serves as adjunct faculty at Belmont University College of Nursing, with prior faculty appointments at Michigan State University and Marian University. As a national speaker and consultant, she serves in leadership as co-chair of Psych Congress Elevate and brings her clinical and research expertise to stages and institutions across the country.

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