What You Should Know About Treatment-Resistant Depression

Treatment-resistant depression (TRD) affects millions of Americans, yet many patients cycle through years of failed treatments before accessing newer options.¹ New real-world data and a landmark regulatory change are prompting fresh questions about how esketamine (Spravato; Janssen Pharmaceuticals) nasal spray fits into the care pathway—and whether managed care policies are keeping pace.

Tamara Werner-Kiechle, MD, therapeutic area head for Neuroscience, Cardiopulmonary and Early Portfolio at Johnson & Johnson, addresses the key questions in a written interview with The American Journal of Managed Care^® (AJMC^®).

What Makes TRD Different From Depression That Responds to Standard Treatment?

TRD is defined by failure to respond to at least 2 adequately dosed antidepressant courses during the same depressive episode. The burden on patients is significant—and often compounding. In the ECHO (54135419TRD4008) real-world study, the largest European dataset on esketamine to date, enrolled patients had accumulated a mean of 3.8 prior treatment failures and had been living with depressive episodes lasting more than 3 years at enrollment.

“Indeed, almost 47% of patients were not working at the beginning of the study,” said Werner-Kiechle. “Therefore, the improvements to MADRS [Montgomery-Asberg Depression Rating Scale] score seen across treatment represent an important outcome for these patients.”

What Did the ECHO Study Find, and Why Does It Matter For Real-World Practice?

ECHO enrolled 570 adults with TRD across 7 countries in Europe and Israel, with no patient exclusions—meaning the cohort included the clinically complex patients that randomized controlled trials typically screen out, including those with psychiatric comorbidities, which affected 45.6% of participants.² Treatment with esketamine nasal spray produced significant and progressive reductions in depressive symptom scores: a mean Montgomery-Asberg Depression Rating Scale (MADRS) decrease of –10.3 points by week 4, –14.4 points by week 12, and –17.6 points by week 48.

Importantly, no new safety signals emerged, and observed adverse events were consistent with the established profile of esketamine nasal spray.

What Does the ECHO Data Show About Durability After Treatment Ends?

This is where ECHO breaks new ground. Of the 570 patients in the study, 301 entered a 6-month post-treatment follow-up period. The mean change in MADRS score from follow-up baseline to week 24 was just –1.4 points, indicating that symptom stability held across the full 6 months after esketamine was discontinued.¹

"The ECHO study is unique in that, for the first time, we have evaluated the durability of effect in real-world practice after stopping esketamine nasal spray treatment in patients with treatment-resistant depression," said Werner-Kiechle.

For managed care, this changes the cost-value framing: esketamine is not assumed to be an indefinite therapy but a time-limited intervention whose benefits persist well beyond active treatment.³

How Should Managed Care Organizations Interpret the Treatment Duration Data?

Although the mean treatment period in ECHO was approximately 9 months, there was meaningful individual variability—23.2% of patients continued for over a year, while others finished earlier. Werner-Kiechle emphasized that duration should not be treated as a fixed variable. All treatment decisions, including when to discontinue, should be made on an individualized basis by health care professionals in alignment with treatment guidelines and to best fit each patient's needs.

"We know from previous studies that the more steps of treatment you have, the lower the chance of coming to remission," said Christine Reif-Leonhard, MD, head of the TRD unit at University Hospital Frankfurt, in an interview with AJMC. "I would not wait 5 or 6 or 7 cycles in advance. We should try to implement it as a third-line therapy."

What Does the January 2025 FDA Monotherapy Approval Change For Patients and Clinicians?

The FDA's approval of esketamine as the first monotherapy for TRD removed the previous requirement that it be coadministered with an oral antidepressant. This is particularly relevant for patients with significant intolerance to oral antidepressants, those managing high pill burden, or those requiring rapid relief.

"We are pleased that esketamine nasal spray has been granted approval for use as a monotherapy for people living with TRD in the US and believe it offers an important additional treatment option for health care professionals and patients living with TRD," said Werner-Kiechle.

What Is the Most Important Unanswered Question In This Field?

Werner-Kiechle pointed to the need for continued evolution of the TRD care paradigm overall. With many patients still experiencing multiple treatment failures and significant functional impairment, the priority is ensuring that patients receive earlier and more effective care to improve their quality of life.

“TRD remains an area of high unmet need for patients, with many patients experiencing multiple prior treatment failures and high impairment on their daily functioning (such as in the ECHO study population),” said Werner-Kiechle. “It is therefore important that we continue to evolve the care paradigm so that patients can receive earlier and more effective care to reduce this impact and improve their overall quality of life.”

References

1. New Spravato (esketamine nasal spray) data support robust effectiveness and show durable effect for treatment resistant depression in a real-world setting. News release. Johnson & Johnson. March 28, 2026. Accessed April 24, 2026. https://www.jnj.com/innovativemedicine/emea/media-center/press-releases/new-spravato-esketamine-nasal-spray-data-support-robust-effectiveness-and-show-durable-effect-for-treatment-resistant-depression-in-a-real-world-setting

2. Steinzor P. Esketamine nasal spray shows rapid, durable effectiveness in treatment-resistant depression. AJMC. April 1, 2026. Accessed April 24, 2026. https://www.ajmc.com/view/esketamine-nasal-spray-shows-rapid-durable-effectiveness-in-treatment-resistant-depression

3. Steinzor P. When the label changes, do coverage policies follow? AJMC. April 14, 2026. Accessed April 24, 2026. https://www.ajmc.com/view/when-the-label-changes-do-coverage-policies-follow-