Pretreatment neurophysiological and clinical characteristics of placebo responders in treatment trials for major depression

Psychopharmacology (Berl). 2004 Dec;177(1-2):15-22. doi: 10.1007/s00213-004-1919-2. Epub 2004 Jul 14.


Rationale: High placebo response rates are a confound in treatment trials for major depressive disorder (MDD). A method for prospective identification of placebo responders could enhance the efficiency of clinical trials.

Objective: The objective was to identify the neurophysiological, symptomatic, and cognitive characteristics of subjects who were likely to respond to placebo in clinical trials for MDD.

Methods: Fifty-one subjects with MDD were treated in clinical trials with either fluoxetine ( n=24) or venlafaxine ( n=27) versus placebo. All subjects underwent pretreatment assessment with quantitative electroencephalographic (QEEG) power and cordance, as well as symptom ratings and neuropsychological testing. After a 1-week single-blind placebo lead-in, subjects were randomized to double-blind placebo controlled treatment with a medication or placebo. At the end of 8 weeks, the blind was broken and treatment response assessed. Response was defined by a final Hamilton Depression Rating Scale score of </=10.

Results: Of the medication-treated and placebo-treated subjects, 52% (13/25) and 38% (10/26) responded. Placebo responders had lower pretreatment frontocentral cordance in the theta frequency band than all other subjects ( P<0.006) and medication responders in particular ( P<0.004). Placebo responders also had faster cognitive processing time, as assessed by neuropsychological testing, and lower reporting of late insomnia ( P<0.03). Exploratory examination of a multiple variable model for predicting placebo response was conducted using logistic regression, in which these three pretreatment measures accurately identified 97.6% of eventual placebo responders.

Conclusions: These findings suggest that combined clinical, neurophysiological, and cognitive assessments of prospective subjects for clinical trials may be useful for identifying MDD subjects who are likely to show robust response to placebo. Prospective validation of these results in a larger, independent sample of subjects is necessary to establish the reliability and usefulness of this method for prospective identification of placebo responders.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Brain / drug effects
  • Brain / physiology*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / psychology*
  • Double-Blind Method
  • Female
  • Fluoxetine / administration & dosage*
  • Humans
  • Male
  • Middle Aged
  • Placebo Effect
  • Psychiatric Status Rating Scales / statistics & numerical data
  • Single-Blind Method


  • Fluoxetine