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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

Published online by Cambridge University Press:  18 June 2025

Víctor Pérez Open the ORCID record for Víctor Pérez [Opens in a new window] ,
Dolors Puigdemont ,
Javier de Diego-Adeliño Open the ORCID record for Javier de Diego-Adeliño [Opens in a new window] ,
Matilde Elices Open the ORCID record for Matilde Elices [Opens in a new window] ,
Itziar Leal Open the ORCID record for Itziar Leal [Opens in a new window] ,
Maria Cabello Open the ORCID record for Maria Cabello [Opens in a new window] ,
Roberto Rodriguez-Jimenez Open the ORCID record for Roberto Rodriguez-Jimenez [Opens in a new window] ,
Miguel Ángel Álvarez-Mon Open the ORCID record for Miguel Ángel Álvarez-Mon [Opens in a new window] ,
Lorena García-Fernández Open the ORCID record for Lorena García-Fernández [Opens in a new window]  and
Eduardo José Aguilar García-Iturrospe
...Show all authors
Víctor Pérez
Affiliation:
Instituto de Salud Mental, Hospital del Mar, Barcelona, Spain Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Dolors Puigdemont
Affiliation:
Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain Psychiatric Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Sant Pau Mental Health, Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Javier de Diego-Adeliño*
Affiliation:
Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain Psychiatric Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Sant Pau Mental Health, Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Matilde Elices*
Affiliation:
Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Itziar Leal
Affiliation:
Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, IIS Princesa, Madrid, Spain Department of Psychiatry, Universidad Autónoma de Madrid, Madrid, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Maria Cabello
Affiliation:
Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, IIS Princesa, Madrid, Spain Department of Psychiatry, Universidad Autónoma de Madrid, Madrid, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Roberto Rodriguez-Jimenez
Affiliation:
Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain Instituto de Investigación 12 de Octubre (i+12), Department of Psychiatry, Hospital Universitario 12 de Octubre, Madrid, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Miguel Ángel Álvarez-Mon
Affiliation:
Departmento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain Departmento de Psiquiatría y Salud Mental, Hospital Universitario Infanta Leonor, Madrid, Spain
Lorena García-Fernández
Affiliation:
Departamento de Medicina Clínica, Universidad Miguel Hernández Alicante, Spain Servicio de Psiquiatría, Hospital Universitario de San Juan Alicante, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Eduardo José Aguilar García-Iturrospe
Affiliation:
Hospital Clínico Universitario de Valencia, Fundación Investigación Hospital Clínico de Valencia, INCLIVA, Valencia, Spain Department of Medicine, University of Valencia, Valencia, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Maria José Escartí
Affiliation:
Hospital Clínico Universitario de Valencia, Fundación Investigación Hospital Clínico de Valencia, INCLIVA, Valencia, Spain Department of Medicine, University CEU-UCH, Valencia, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Angel Luis Montejo
Affiliation:
Servicio de Psiquiatría, Hospital Clínico Universitario, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
José Manuel Montes
Affiliation:
Departmento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain Servicio de Psiquiatría, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Judith Usall
Affiliation:
Parc sanitari Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Hospitalet de Llobregat, Spain
Ascensión Gallego-Nogueras
Affiliation:
Servicio de Psiquiatría, Hospital Clínico Universitario, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
Elena Lujan
Affiliation:
Servicio de Psiquiatría, Hospital Universitario del Sureste, Madrid, Spain
Raquel López-Carrilero
Affiliation:
Parc sanitari Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Hospitalet de Llobregat, Spain
Ana González-Pinto
Affiliation:
Department Psychiatry, Hospital Universitario Alava, Vitoria, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Agurtzane Ortiz-Jauregui
Affiliation:
Department Psychiatry, Hospital Universitario Alava, Vitoria, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Jordi Blanch
Affiliation:
Mental Health and Addiction Services, Hospital Universitari de Santa Maria de Lleida, Lleida, Spain Department of Psychiatry and Psychology, Hospital Clinic of Barcelona, Barcelona, Spain Clinical Sciences Department, University of Barcelona (UB), Barcelona, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Mikel Urretavizcaya
Affiliation:
Clinical Sciences Department, University of Barcelona (UB), Barcelona, Spain Bellvitge University Hospital – ICS, Psychiatry, Bellvitge Biomedical Research Institute IDIBELL, Neurosciences Group-Psychiatry and Mental Health, L’Hospitalet de Llobregat, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Francesc Colom
Affiliation:
Instituto de Salud Mental, Hospital del Mar, Barcelona, Spain Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
Javier García-Campayo
Affiliation:
Institute of Health Research of Aragon (IIS Aragón), Miguel Servet University Hospital, Zaragoza, Spain Research Network on Chronicity, Primary Care and Health Promotion (RICAPPS), Zaragoza, Spain Psychiatry Department, Faculty of Medicine, University of Zaragoza, Zaragoza, Spain
José Luis Ayuso-Mateos
Affiliation:
Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, IIS Princesa, Madrid, Spain Department of Psychiatry, Universidad Autónoma de Madrid, Madrid, Spain Centro de Investigación Biomédica en Red (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
*
Correspondence: Javier de Diego-Adeliño. Email: FranciscoJavier.DeDiego@uab.cat; Matilde Elices. Email: melices@researchmar.net
Correspondence: Javier de Diego-Adeliño. Email: FranciscoJavier.DeDiego@uab.cat; Matilde Elices. Email: melices@researchmar.net
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Abstract

Background

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), but initial outcomes can be modest.

Aims

To compare SSRI dose optimisation with four alternative second-line strategies in MDD patients unresponsive to an SSRI.

Method

Of 257 participants, 51 were randomised to SSRI dose optimisation (SSRI-Opt), 46 to lithium augmentation (SSRI+Li), 48 to nortriptyline combination (SSRI+NTP), 55 to switch to venlafaxine (VEN) and 57 to problem-solving therapy (SSRI+PST). Primary outcomes were week-6 response/remission rates, assessed by blinded evaluators using the 17-item Hamilton Depression Rating Scale (HDRS-17). Changes in HDRS-17 scores, global improvement and safety outcomes were also explored. EudraCT No. 2007-002130-11.

Results

Alternative second-line strategies led to higher response (28.2% v. 14.3%, odds ratio = 2.36 [95% CI 1.0–5.6], p = 0.05) and remission (16.9% v. 12.2%, odds ratio = 1.46, [95% CI 0.57–3.71], p = 0.27) rates, with greater HDRS-17 score reductions (−2.6 [95% CI −4.9 to −0.4], p = 0.021]) than SSRI-Opt. Significant/marginally significant effects were only observed in both response rates and HDRS-17 decreases for VEN (odds ratio = 2.53 [95% CI 0.94–6.80], p = 0.067; HDRS-17 difference: −2.7 [95% CI −5.5 to 0.0], p = 0.054) and for SSRI+PST (odds ratio = 2.46 [95% CI 0.92 to 6.62], p = 0.074; HDRS-17 difference: −3.1 [95% CI −5.8 to −0.3], p = 0.032). The SSRI+PST group reported the fewest adverse effects, while SSRI+NTP experienced the most (28.1% v. 75%; p < 0.01), largely mild.

Conclusions

Patients with MDD and insufficient response to SSRIs would benefit from any other second-line strategy aside from dose optimisation. With limited statistical power, switching to venlafaxine and adding psychotherapy yielded the most consistent results in the DEPRE'5 study.

Keywords

Major depressive disordertreatment resistant depressionselective serotonin reuptake inhibitorsantidepressantspsychotherapy
Type
Original Article
Information
The British Journal of Psychiatry , First View , pp. 1 - 8
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Copyright
© The Author(s), 2025. Published by Cambridge University Press on behalf of Royal College of Psychiatrists

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