doi:10.1192/bjp.2025.13engPérez, VíctorPuigdemont, Dolorsde Diego-Adeliño, JavierElices, MatildeLeal, ItziarCabello, MariaRodriguez-Jimenez, RobertoÁlvarez-Mon, Miguel ÁngelGarcía-Fernández, LorenaAguilar García-Iturrospe, Eduardo JoséEscartí, Maria JoséMontejo, Angel LuisMontes, José ManuelUsall, JudithGallego-Nogueras, AscensiónLujan, ElenaLópez-Carrilero, RaquelGonzález-Pinto, AnaOrtiz-Jauregui, AgurtzaneBlanch, JordiUrretavizcaya, MikelColom, FrancescGarcía-Campayo, JavierAyuso-Mateos, José LuisThe 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 treatmentART-2025-144641Background 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.2025http://zaguan.unizar.es/record/16198410.1192/bjp.2025.13http://zaguan.unizar.es/record/161984oai:zaguan.unizar.es:161984info:eu-repo/grantAgreement/ES/ISCIII/FIS/EC07-90244BRITISH JOURNAL OF PSYCHIATRY (2025), 8All rights reservedhttp://www.europeana.eu/rights/rr-f/info:eu-repo/semantics/openAccess