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

The British Journal of Psychiatry Pub Date : 2025-06-18 DOI:10.1192/bjp.2025.13

Víctor Pérez, Dolors Puigdemont, Javier de Diego-Adeliño, Matilde Elices, Itziar Leal, Maria Cabello, Roberto Rodriguez-Jimenez, Miguel Ángel Álvarez-Mon, Lorena García-Fernández, Eduardo José Aguilar García-Iturrospe, Maria José Escartí, Angel Luis Montejo, José Manuel Montes, Judith Usall, Ascensión Gallego-Nogueras, Elena Lujan, Raquel López-Carrilero, Ana González-Pinto, Agurtzane Ortiz-Jauregui, Jordi Blanch, Mikel Urretavizcaya, Francesc Colom, Javier García-Campayo, José Luis Ayuso-Mateos

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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.

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DEPRE ' 5研究：实用、多中心、五组、平行组随机对照试验，采用盲法评估，比较选择性血清素再摄取抑制剂治疗失败后重度抑郁症的治疗策略

选择性5 -羟色胺再摄取抑制剂（SSRIs）是重度抑郁症（MDD）的一线治疗方法，但最初的效果可能并不理想。目的比较SSRI剂量优化与对SSRI无反应的MDD患者的四种备选二线策略。方法257名参与者中，51人随机分为SSRI剂量优化组（SSRI- opt）， 46人随机分为锂离子增强组（SSRI+Li）， 48人随机分为去甲替林联合组（SSRI+NTP）， 55人随机分为文拉法辛组（VEN）， 57人随机分为问题解决治疗组（SSRI+PST）。主要结果是第6周的缓解/缓解率，由盲法评估者使用17项汉密尔顿抑郁评定量表（HDRS-17）评估。还探讨了HDRS-17评分、总体改善和安全性结果的变化。草案号2007-002130-11。结果与SSRI-Opt相比，其他二线治疗方案的缓解率（28.2% vs . 14.3%，优势比= 2.36 [95% CI 1.0 ~ 5.6], p = 0.05）和缓解率（16.9% vs . 12.2%，优势比= 1.46,[95% CI 0.57 ~ 3.71], p = 0.27）更高，HDRS-17评分降低率（- 2.6 [95% CI - 4.9 ~ - 0.4], p = 0.021]）更高。仅在VEN的应答率和HDRS-17降低方面观察到显著/边际显著的影响(优势比= 2.53 [95% CI 0.94-6.80], p = 0.067；HDRS-17差异：- 2.7 [95% CI - 5.5 ~ 0.0], p = 0.054)和SSRI+PST(优势比= 2.46 [95% CI 0.92 ~ 6.62], p = 0.074；HDRS-17差异：−3.1 [95% CI−5.8 ~−0.3],p = 0.032)。SSRI+PST组不良反应最少，而SSRI+NTP组不良反应最多(28.1% vs . 75%；p & lt;0.01)，基本上是温和的。结论重度抑郁症患者对SSRIs反应不足，除了剂量优化外，任何其他二线策略都可以使患者受益。由于统计能力有限，在DEPRE'5研究中，改用文拉法辛并增加心理治疗产生了最一致的结果。

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The British Journal of Psychiatry

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