Determinants of Nonspecific Response to Treatment in Randomized Controlled Trials of Major Depressive Disorder: A Narrative Review.

Clotilde Guidetti; Riccardo De Giorgi; Nathan T M Huneke; Franco De Crescenzo; Chiara Zippi; George I Papakostas; Maurizio Fava

doi:10.1176/appi.ajp.20251233

PubMed · 42522066

Determinants of Nonspecific Response to Treatment in Randomized Controlled Trials of Major Depressive Disorder: A Narrative Review.

Clotilde Guidetti·Riccardo De Giorgi·Nathan T M Huneke·Franco De Crescenzo·Chiara Zippi·George I Papakostas·Maurizio Fava

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Abstract

The design, conduct, and interpretation of double-blind randomized placebo-controlled clinical trials in major depressive disorder (MDD) are complicated by determinants of nonspecific response to treatment (NSRT). This narrative review provides a comprehensive overview of the determinants of NSRT in randomized controlled trials (RCTs) for MDD, including the placebo effect, factors related to measurement of the primary endpoint, the inclusion of misdiagnosed patients, the relapsing-remitting course of MDD, and factors related to functional unblinding. Potential strategies to reduce the impact of the determinants of NSRT and to improve the interpretation of RCT outcomes in MDD are also summarized. These strategies include use of centralized rating and standardized rater training, independent diagnostic confirmation, optimized site selection, minimizing financial incentives, exclusion of subjects participating in multiple clinical trials, exclusion of patients with unstable major depressive episode trajectories, and use of active placebo and alternative trial designs. Uniformity among experts in the definitions of determinants of NSRT and related concepts, as well as in strategies to address them, may facilitate progress in the development of novel treatments for MDD.

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Humans Major Depressive Disorder Randomized Controlled Trials as Topic Antidepressive Agents Treatment Outcome Placebo Effect Research Design Clinical Drug Studies Depressive Disorders Journal Article Review

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Clotilde Guidetti, Riccardo De Giorgi, Nathan T M Huneke, Franco De Crescenzo, Chiara Zippi, George I Papakostas, Maurizio Fava. 2026-07-29. Determinants of Nonspecific Response to Treatment in Randomized Controlled Trials of Major Depressive Disorder: A Narrative Review.. https://doi.org/10.1176/appi.ajp.20251233

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Journal Article; Review resource Antidepressive Agents subject Humans subject Journal Article subject Major Depressive Disorder subject Placebo Effect subject

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