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11/08/2025 - Institutional news

Optimizing Antidepressant Dosage in Patients with Treatment-Resistant Depression Is Less Effective Than Switching or Combining Therapies

A recently published randomized clinical trial has shown that switching antidepressants or combining medication with psychotherapy may be more effective than simply increasing the dose when a first treatment with a selective serotonin reuptake inhibitor (SSRI) fails in patients with treatment-resistant depression. The study, named DEPRE'5, was led by Dr. Víctor Pérez Sola, Head of the Psychiatry Department at Hospital del Mar, and José Luis Ayuso, from the Autonomous University of Madrid, both group leaders within the CIBER Mental Health area (CIBERSAM).

SSRIs are commonly prescribed as the first-line treatment for depression, but they often have limited effectiveness. This study, published in The British Journal of Psychiatry, explored what steps to take when SSRIs do not produce adequate results. A total of 257 individuals diagnosed with major depressive disorder and showing insufficient response to an SSRI participated in the study.

The researchers compared five treatment strategies: SSRI dose optimization (control group), switching to venlafaxine (another antidepressant), combining with lithium (a mood stabilizer), combining with nortriptyline (a tricyclic antidepressant), Adding problem-solving focused psychotherapy. After six weeks, patients in the alternative strategy groups showed higher rates of clinical response (28.2%) compared to those in the dose optimization group (14.3%), along with a greater reduction in symptoms based on the Hamilton Depression Rating Scale.

Although not all differences between groups reached statistical significance, the most consistent improvements were observed in patients who switched to venlafaxine or added psychotherapy, with the latter also resulting in fewer side effects. "Our data suggest that when a first antidepressant treatment fails, there are other options that may be more effective. Considering a personalized approach that combines medication and therapy can make a big difference in treating depression," explains Dr. Víctor Pérez, first author of the article.

The study was designed as a pragmatic, multicenter, blinded-assessment randomized controlled trial, in line with international clinical research standards. It was conducted across ten hospitals within the Spanish National Health System, with funding from the Carlos III Health Institute. The trial involved several CIBERSAM research groups, with researchers from a range of healthcare and academic institutions, including: Hospital de la Santa Creu i Sant Pau, Hospital Universitario 12 de Octubre, Faculty of Medicine, University of Valencia, Hospital Ramón y Cajal, Institut de Recerca Sant Joan de Déu, Hospital Universitario de Álava, Hospital Clínic de Barcelona, Hospital Universitario de Bellvitge - IDIBELL.

Artículo de referencia:

Pérez V, Puigdemont D, de Diego-Adeliño J, Elices M, Leal I, Cabello M, Rodriguez-Jimenez R, Álvarez-Mon MÁ, García-Fernández L, Aguilar García-Iturrospe EJ, Escartí MJ, Montejo AL, Montes JM, Usall J, Gallego-Nogueras A, Lujan E, López-Carrilero R, González-Pinto A, Ortiz-Jauregui A, Blanch J, Urretavizcaya M, Colom F, García-Campayo J, Ayuso-Mateos JL. The DEPRE'5 study: pragmatic, multicentre, five-arm, parallel-group randomised controlled trial with blinded assessment to compare treatment strategies in major depression after a failed selective serotonin reuptake inhibitor treatment. Br J Psychiatry. 2025 Jun 18:1-8. doi: 10.1192/bjp.2025.13. Epub ahead of print. PMID: 40530754.

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