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. 2025 Jun 18;227(5):1-8.
doi: 10.1192/bjp.2025.13. Online ahead of print.

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

Víctor Pérez  1   2   3   4 , Dolors Puigdemont  5   6   7   4 , Javier de Diego-Adeliño #  5   6   7   4 , Matilde Elices #  2   4 , Itziar Leal  8   9   4 , Maria Cabello  8   9   4 , Roberto Rodriguez-Jimenez  10   11   4 , Miguel Ángel Álvarez-Mon  12   13   14 , Lorena García-Fernández  15   16   4 , Eduardo José Aguilar García-Iturrospe  17   18   4 , Maria José Escartí  17   19   4 , Angel Luis Montejo  20 , José Manuel Montes  12   21   4 , Judith Usall  22 , Ascensión Gallego-Nogueras  20 , Elena Lujan  23 , Raquel López-Carrilero  22 , Ana González-Pinto  24   4 , Agurtzane Ortiz-Jauregui  24   4 , Jordi Blanch  25   26   27   4 , Mikel Urretavizcaya  27   28   4 , Francesc Colom  1   2   4 , Javier García-Campayo  29   30   31 , José Luis Ayuso-Mateos  8   9   4
Affiliations

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

Víctor Pérez et al. Br J Psychiatry. .

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 disorder; antidepressants; psychotherapy; selective serotonin reuptake inhibitors; treatment resistant depression.

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Conflict of interest statement

V.P. has received grants and served as consultant, advisor or continuing medical education (CME) speaker for AB-Biotics, Almirall, AstraZeneca, Bristol-Myers Squibb, Compass, Johnson & Johnson, Lundbeck, Medtronic, Merk, Otsuka, Pfizer, Solvay, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute) and the Servei Català de Salud (Generalitat de Catalunya). J.D.D.A has received grants from the Spanish Ministry of Health Instituto de Salud Carlos III (PI23/00469) and the Health Research and Innovation Strategic Plan (PERIS; SLT008/18/00207) of the Generalitat de Catalunya and served as an advisor or CME speaker for Johnson & Johnson, Lundbeck, Pfizer, Neuraxpharm, Esteve, Viatris and Amgen. J.B has received consulting fees from Idorsia, honoraria for speaking and teaching from GILEAD and Menarini, grants for conference registration and travel and hosting costs from Johnson & Johnson, MSD and ViiV Healthcare, with no financial or other relationship relevant to the subject of this article. A.G.P has received grants and served as a consultant, advisor or CME speaker for the following entities: Johnson & Johnson, Lundbeck, Otsuka, Angelini, Exeltis, Novartis, Rovi, Takeda, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute), the Basque Government and the European Framework Programme of Research. J.M.M. has received research funding from Johnson & Johnson, the Carlos III Health Institute and Otsuka-Lundbeck; in the last 5 years, he has had agreements or received fees as a speaker from Exeltis, Lundbeck, Angelini, Johnson & Johnson, Neuraxpharm, Pfizer, Servier, Rovi and Recordati. R.R.J has been a consultant for, spoken on activities of or received grants from Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid Regional Government (S2010/ BMD-2422 AGES; S2017/BMD-3740), Johnson & Johnson, Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Casen-Recordati, Angelini and Rovi. All other authors have no interests to declare.

Figures

Fig. 1
Fig. 1
Flow diagram for study participants. SSRI, serotonin reuptake inhibitor; Opt, dose optimisation; Li, lithium; NTP, nortriptyline; PST, problem-solving therapy; VEN, venlafaxine; ITT, intention to treat.
Fig. 2
Fig. 2
Response/remission rates at week 6 and mean Hamilton Depression Rating Scale (HDRS) score change from baseline. SSRI, serotonin reuptake inhibitor; Opt, dose optimisation; Li, lithium; NTP, nortriptyline; PST, problem-solving therapy; VEN, venlafaxine; ITT, intention to treat; MMRM, mixed model for repeated measures.
Fig. 3
Fig. 3
Incidence of adverse effects occurring in more than 5% of patients in each treatment group. SSRI, serotonin reuptake inhibitor; Opt, dose optimisation; Li, lithium; NTP, nortriptyline; PST, problem-solving therapy; VEN, venlafaxine.
See this image and copyright information in PMC

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