Early Placebo Response May Yield More Meaningful Data in Major Depressive Disorder Trials

Researchers found that in a study of major depressive disorder, patients who had an early score fluctuation regardless of treatment may adversely affect the assessment of the treatment outcome.

Placebo-controlled trials of major depressive disorder (MDD) drugs often feature high placebo response rates, and placebo-assigned patients with MDD in these trials who have a ≥20% depression total score fluctuation (improvement or worsening) during a double-blind placebo lead-in period show higher 8-week rates of placebo response, as well as remission, compared with placebo-treated patients with a <20% score fluctuation, according to a study published in the Journal of Psychiatric Research.

This study was an analysis of data from the multicenter, randomized, double-blinded, phase 2 Horizon study (NCT01912196), which examined the efficacy and safety of s-adenosyl methionine 800 mg (MSI-195) plus an ongoing antidepressant in patients with MDD.

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Patients in the intention-to-treat population were randomly assigned to either MSI-195 (n=117) or placebo (n=110). Efficacy was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton rating scale for depression (HamD17). The total MADRS and HamD17 score trajectories were examined for all placebo-assigned patients. In addition, researchers evaluated the overall score changes of the mean MADRS and HamD17 scores at week 8 compared with the MADRS and HamD17 fluctuation between week 0 and week 2.

There was a significantly less overall improvement by week 8 in the 101 patients with a <20% early HamD17 score fluctuation vs patients with a ≥20% score fluctuation between 0 and 2 weeks (P <.0001). Approximately 85.4% of patients who met criteria for HamD17 placebo response at week 2 remained responsive to placebo at week 8 compared with 30.4% of patients with <20% HamD17 fluctuation between 0 and 2 weeks (P <.0001).

In addition, there was significantly less overall improvement by week 8 in patients with a <20% early MADRS score fluctuation compared with patients with a ≥20% MADRS score fluctuation between weeks 0 and 2 (P <.0001). In a post hoc analysis of 217 evaluable patients in the intention-to-treat population without a ≥20% early score response, higher effect sizes for HamD17 and MADRS favoring MSI-195 over placebo were observed. The analysis also found a statistically significant benefit of MSI-195 over placebo in the MADRS subgroup (effect size, 0.404; P =.012).

A limitation of the analysis included its reliance on only 1 study, warranting the need for future prospective validation from other studies.

The researchers concluded that “study designs that anticipate and attempt to manage early response prior to randomization may yield more meaningful outcome data for trials of MDD and possibly other disorders as well.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Targum SD, Cameron BR, Ferreira L, MacDonald ID. Early score fluctuation and placebo response in a study of major depressive disorder. J Psychiatr Res. 2019;121:118-125.