Maurizio Fava, MD

Is the placebo effect the biggest obstacle to developing new antidepressants?

A new narrative review suggests that while the placebo effect is one of the best-known challenges in depression research, it is only one of several factors that can affect clinical trial results.

An international team of researchers, led by first author Clotilde Guidetti, MD, and senior author Maurizio Fava, MD, of Mass General Brigham, examined determinants of nonspecific response to treatment (NSRT) in double-blind randomized controlled trials (RCTs) for major depressive disorder.

NSRT refers to factors that can influence trial outcomes independent of a treatment’s intended effect. Although RCTs are considered the gold standard for evaluating new therapies, these sources of nonspecific response can make trial results more difficult to interpret and complicate the evaluation of potential antidepressants.

Clotilde Guidetti, MD

The review highlights treatment perceptibility as one particularly important source of bias, noting that noticeable treatment effects can lead to functional unblinding (when participants or researchers can infer who received the treatment versus a placebo) and influence trial outcomes, potentially disadvantaging less perceptible therapies.

To help address these challenges, the authors outline strategies to strengthen future depression trials, including standardized rater training, independent diagnostic confirmation, improved participant selection and alternative trial designs.

They conclude that greater consistency in how researchers define and address NSRT could improve the reliability of depression trials and support the development of novel treatments.

Published in American Journal of Psychiatry on July 29, 2026 | Read the paper: Determinants of Nonspecific Response to Treatment in Randomized Controlled Trials of Major Depressive Disorder: A Narrative Review

Summary reviewed by: Clotilde Guidetti, MD, lead author; George Papakostas, MD, co-author; Maurizio Fava, MD, senior author