Introduction

Treatment-resistant depression remains one of the most significant challenges in behavioral health. Patients with treatment-resistant depression experience persistent depressive symptoms despite adequate trials of conventional antidepressant medications, and/or evidence-based psychotherapies. This often results in substantial functional impairment, reduced quality of life, and increased risk of suicidality.

Esketamine nasal spray (Spravato®) is an important addition to the depression treatment landscape. It is FDA approved for adults with treatment-resistant depression and can be used with or without an oral antidepressant. It is also FDA approved for depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior (MDSI) when used in combination with an oral antidepressant.1 Treatment is delivered in two phases: an induction phase consisting of twice-weekly treatment for four weeks, followed by maintenance phase with treatment administered once weekly for four weeks followed by treatments every week or every other week. Esketamine has been found to produce meaningful improvement of depressive symptoms in patients who continue to experience symptoms despite conventional pharmacotherapy.2 3

Between January and December 2025, more than 800 patients initiated esketamine treatment with LifeStance, increasing to over 1,000 patients by the end of May 2026. By the end of 2026, LifeStance aims to expand access to esketamine by offering the treatment in 18 states, doubling its footprint for esketamine treatment. The expansion is supported by over 80 highly-trained psychiatric providers qualified to administer esketamine treatment.

Many Patients Experienced Meaningful Improvement

LifeStance examined changes in the Patient Health Questionnaire-9 (PHQ-9) scores among 311 patients with completed esketamine induction treatments between January 1, 2025 and May 31, 2026. The PHQ-9 is a validated, nine-item questionnaire that assesses the severity of depressive symptoms and monitors changes over time.4 Scores range from 0 to 27 with higher scores indicating more severe depression symptoms. The mean age of participants was 40.5 years, with ages ranging from 19 to 82 years. The sample was predominantly female (58%), while 28% identified as male and 6% as transgender, genderqueer, or another gender identity. The sample included patients from a range of racial and ethnic backgrounds, with approximately three quarters (75%) identifying as white.

A total of 300 patients completed the induction phase of the treatment, and 258 patients continued with maintenance treatment at 12 weeks. Patients received a mean of 14 treatments (range of 8 to 20 treatments) 12 weeks after beginning treatment. Of the 258 patients, 74% experienced a clinically meaningful improvement* in depression symptom severity. These findings highlight the effectiveness of esketamine in real-world outpatient practice and its effectiveness in individuals with treatment-resistant depression.

Esketamine (Spravato) Outcomes for Treatment-Resistant Depression

A Closer Look at Depression Outcomes

The most prominent finding in the dataset was a substantial reduction in depressive symptoms as measured by the PHQ-9. The mean pre-treatment PHQ-9 score was 18.6, corresponding to moderately severe depressive symptomatology. Following treatment, the mean PHQ-9 score declined to 12.1 (moderate depression) after four weeks of treatment, corresponding to the induction phase of esketamine treatment. Patients further improved after 12 weeks, with a mean PHQ-9 score of 9.9 (mild depression). This represents an average reduction of 8.7 points, or approximately 47% from baseline. The findings are consistent with emerging real-world evidence supporting the effectiveness of esketamine.3 5

Suicidal Thoughts and Safety Considerations

Meaningful improvements were also observed in suicidal ideation. At the start of treatment, 44% of patients reported no suicidal thoughts on their PHQ-9, while 13% reported experiencing suicidal thoughts nearly every day. After four weeks of treatment, the percentage of patients reporting no suicidal ideation increased to 66%, while the percentage experiencing suicidal thoughts nearly every day fell to 5%. Improvements continued throughout the maintenance phase. By week 12, 76% of patients reported no suicidal ideation, and only 2% reported experiencing suicidal ideation nearly every day. These findings indicate not only a meaningful reduction* in suicidality during the induction phase of treatment, but also sustained and continued improvement over time. The progressive shift toward lower levels of suicidal ideation suggests that treatment benefits extended beyond the initial intervention period, with gains maintained and further enhanced through 12 weeks of care.

Table 1. PHQ-9 Question 9 Responses on Suicidal Ideation Before and After Treatment

Response Before esketamine (baseline) After esketamine, week 4 After esketamine, week 12 Change in Patient % after 12 weeks of treatment
Nearly every day 13% 5% 2% 85% reduction in patients reporting suicidal ideation nearly every day
Not at all 44% 66% 76% 70% increase in patients reporting no suicidal ideation

Clinical Implications

These findings provide compelling, real-world evidence supporting the effectiveness of esketamine for patients experiencing significant depressive symptoms with or without suicidal ideation. Among 258 patients, mean depression severity reduced by nearly 50%, while the frequency of suicidal thoughts also declined substantially. These results contribute to the growing body of evidence demonstrating that intranasal esketamine can produce meaningful clinical improvement among patients with treatment-resistant depression when implemented in routine practice.5 While controlled trials remain essential for establishing comparative efficacy and causality, real-world outcome data such as these findings provide valuable insight into the potential effectiveness of intranasal esketamine in everyday care settings and illustrate the magnitude of clinical improvement that can be achieved.

* Clinically meaningful improvement is defined as PHQ-9 severity score reduction of five or more points

Citations

  1. U.S. Food and Drug Administration. (n.d.). SPRAVATO® (esketamine) nasal spray, CIII Initial U.S. Approval: 1970 (ketamine) (No. 5514350). U.S. Food and Drug Administration. Retrieved https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211243s016lbl.pdf

  2. Marci, C. D., Joshi, K., Severtson, S. G., Breeze, J. L., & Jha, M. K. (2025). Real-world evaluation of change in depressive symptoms among patients with treatment-resistant depression treated with esketamine. BMC Psychiatry, 25(1), 1195. https://doi.org/10.1186/s12888-025-07485-w

  3. Molero, P., Ibañez, A., De Diego-Adeliño, J., Ramos-Quiroga, J. A., García Dorado, M., López Rengel, P. M., & Saiz, P. A. (2025). A Real-World Study on the Use, Effectiveness, and Safety of Esketamine Nasal Spray in Patients with Treatment-Resistant Depression: INTEGRATE Study. Advances in Therapy, 42(5), 2335–2353. https://doi.org/10.1007/s12325-025-03149-z

  4. Kroenke, K., Spitzer, R. L., & Williams, J. B. W. (2001). The PHQ-9: Validity of a brief depression severity measure. Journal of General Internal Medicine, 16(9), 606–613. https://doi.org/10.1046/j.1525-1497.2001.016009606.x

  5. De Oliveira Lapa, C., Viola, T., Delfino, R., Dutra, L., Rubira, G., Rodrigues, R. J. K., Coral, S. C., Ramos-Quiroga, J. A., & Spanemberg, L. (2026). Systematic review and meta-analysis of intranasal esketamine for treatment-resistant depression: Evidence from real-world studies. Journal of Affective Disorders, 401, 121257. https://doi.org/10.1016/j.jad.2026.121257

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Authored By 

Stephanie Eken, MD, MBA

Stephanie Eken, MD, MBA, is a triple board-certified psychiatrist, child and adolescent psychiatrist, and pediatrician with more than 20 years of experience in behavioral health, currently serving as Chief Medical Officer at LifeStance, where she leads clinical strategy and vision...

Authored By Jennifer Park, PhD
Jennifer Park, PhD

Jennifer Park, PhD, is a licensed clinical psychologist, behavioral health executive, and expert in cognitive behavioral therapy (CBT). She serves as Vice President of Clinical Excellence & Innovation at LifeStance Health and is an Adjunct Clinical Associate Professor in the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine. In her leadership role, she advances clinical quality, measurement-based care, and innovation across one of the nation's largest outpatient behavioral health organizations. Prior to joining LifeStance, Dr. Park served as Vice President of Clinical Services at Acadia Healthcare, where she oversaw clinical services across inpatient psychiatric hospitals, residential treatment centers, and substance use disorder treatment programs. Previously, as Executive Director of Outpatient Services at Rogers Behavioral Health, she led clinical services for partial hospitalization and intensive outpatient programs. Across these roles, she has extensive experience translating empirically supported treatments into scalable, sustainable models of care within large healthcare systems. Dr. Park earned her PhD in Clinical Psychology from the University of South Florida and completed her internship and fellowship training at Massachusetts General Hospital/Harvard Medical School. She has authored numerous publications and delivered more than 100 presentations at national, regional, and local professional forums on evidence-based care, implementation science, and behavioral health innovation.

Authored By Stephen Fleming, MD
Stephen Fleming, MD

Dr. Stephen Fleming is a psychiatrist who has been practicing since 2012. He obtained his bachelor's degree at the University of Georgia and his medical school education at the Medical College of Georgia in Augusta, GA. He received training in general psychiatry as well as child and adolescent psychiatry at the Medical College of Georgia while completing his residency and fellowship.Dr. Fleming seeks to utilize his clinical expertise to help those who are struggling with mental illness not only treat their illness to remission but also achieve the sense of well-being and fullness of life they desire. Since 2018 he has been a prescriber of Transcranial Magnetic Stimulation, a non-invasive magnetic therapy approved for the treatment of depression and OCD.In his time away from the office, Dr. Fleming enjoys spending time with his family and his dogs, exercising, reading, watching sports--in particular the Georgia Bulldogs, and traveling.

Authored By Olga Konovalova, Master’s in Finance
Olga Konovalova, Master’s in Finance

As part of the Insights and Analytics team, Olga designs scalable data models and business intelligence solutions that transform complex clinical and operational data into clear, actionable insights to support decision-making across clinical and leadership teams. With a focus on clinical quality and patient outcomes, Olga is passionate about using data to drive meaningful improvements in healthcare delivery.

Authored By Bridget Balkaran, MPH
Bridget Balkaran, MPH

A driven biostatistician with strong analytical skills for EMR data. Focuses on translating statistical results into interpretable solutions by identifying and reporting associations. Experience with machine learning and regression models. A unique combination of technical proficiency and clear communication through storytelling with data to discover solutions.