Abrupt Symptom Improvements in Antidepressant Clinical Trials: Transient Placebo Effects or Therapeutic Reality?

According to prevailing models and classical reports, abrupt responses to antidepressant medication are not true drug responses but rather transient placebo effects. By contrast, recent reports suggest that early sudden improvements have a lasting effect and appear in most patients receiving medication. Clinical guidelines influenced by these contradictory findings are mixed and confusing.

To evaluate the occurrence and effects of abrupt improvements in symptoms in placebo vs antidepressant conditions in individuals with late-life depression, using a rigorous method of identifying sudden gains, developed and tested in scores of studies in psychotherapy research.

We analyzed data (collected during 1999-2002) from 174 patients 75 years or older, with unipolar depression (based on DSM-IV), who were randomly assigned to citalopram or placebo. We tested differences between conditions in the prevalence of sudden gains, and their effect on outcome, using χ² analyses and linear regression models. Pretreatment predictors of sudden gains were identified using a machine learning approach.

36.2% of patients showed stable sudden gains, without significant differences between medication and placebo conditions (χ²₁ = 0.95, P = .33). The mean reduction in the Hamilton Depression Rating Scale score was 7.2 points greater for patients who showed sudden gains (t₁₇₂ = -7.52, P < .0001). Higher levels of pretreatment symptom severity and higher processing speed increased the likelihood of showing sudden gains.

Even in a geriatric population, which is likely to show more sustained depression and less fluctuation, sudden gains were common. The findings may necessitate modifying current models of mechanisms of change of antidepressant medication and may affect guidelines for best clinical practice.