Impact of Difficult-to-Treat-Depression for Patients and Society: a Real-World Study

Sergio Benavente¹Alba Parra¹Jorge Lopez-Castroman^2,3,4,5,6,7Ismael Conejero^10,11,8,9*Pablo Alonso-Torres¹²Tatiana Caraballo López¹²Pablo Carrasco Arteaga¹²Enrique Baca-García^{1,10,11,13,14,15,16,7,9}

• ¹Hospital Universitario Infanta Elena, Valdemoro, Spain
• ²Universidade de Santiago de Compostela, Santiago de Compostela, Spain
• ³Centre Hospitalier Universitaire de Nimes, Nimes, France
• ⁴Institut de Genomique Fonctionnelle, Montpellier, France
• ⁵Universite de Montpellier, Montpellier, France
• ⁶CNRS-INSERM, Montpellier, France
• ⁷Centro de Investigacion Biomedica en Red de Salud Mental, Madrid, Spain
• ⁸Centre Hospitalier Universitaire de Nîmes, Nîmes, France
• ⁹Instituto de Investigacion Sanitaria de la Fundacion Jimenez Diaz, Madrid, Spain
• ¹⁰Universidad Autonoma de Madrid, Madrid, Spain
• ¹¹Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain
• ¹²Johnson & Johnson, Madrid, Spain
• ¹³Hospital Rey Juan Carlos, Móstoles, Spain
• ¹⁴Hospital Universitario General de Villalba, Collado Villalba, Madrid, Spain
• ¹⁵Universidad Catolica del Maule, Talca, Chile
• ¹⁶Centre Hospitalier Universitaire de Montpellier, Montpellier, France

Background: Treatments and evolution of depressive disorders are highly heterogeneous, with Difficult-to-Treat Depression (DTD) presenting elevated medical and economic burdens, particularly when accompanied by suicidality. This study analyzed clinical profiles, evolution, and costs associated with Major Depressive Disorder (MDD), MDD with Suicide Risk (MDD-SR), DTD, and DTD with Suicide Risk (DTD-SR) over 12 months, considering initial healthcare pathways. Methods: A cohort of 3,941 individuals aged ≥18 years was recruited between 2014–2018 in four Madrid hospitals. Patients were classified according to their first contact with mental health services through emergency settings (emergency-first) or outpatient settings (outpatient-first). Sociodemographic data, ICD-10 diagnoses, and healthcare resource use were extracted from electronic health records and the MeMind digital ecosystem. Suicide risk was assessed via MINI-based suicide risk assessment, and clinical profiles and costs were compared. Results: Compared with outpatient-first patients, emergency-first patients showed greater depression severity, psychiatric comorbidities, and suicide risk versus outpatient-first patients (p<0.001 respectively), along with increased rates of DTD (p=0.021), poorer treatment outcomes, and higher global costs. Patients with DTD or suicide risk displayed greater depression severity, lower treatment response and more frequent relapses, psychiatric hospitalization, and antidepressant augmentation strategies compared to MDD-only patients. Emergency-first DTD-SR patients incurred the highest costs (€15,358.1 [SD=16,415.1]/patient/year). Suicide risk was strongly associated with probable relapses and DTD. Conclusions: Despite high economic expenses, important needs remain unmet for DTD, especially for patients showing suicide risk with a first contact through the emergency setting. Earlier detection, innovative treatments, improved access to healthcare, and integration in mobile health programs should mitigate these gaps and improve clinical outcomes in this vulnerable population.