© 2016 Schalet et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: Meta-analyses of placebo-controlled trials of SSRIs suggest that only a small portion of the observable change in depression may be attributed to "true" pharmacological effects. But depression is a multidimensional construct, so treatment effects may differ by symptom cluster. We tested the hypothesis that SSRIs uniquely alter psychological rather than somatic symptoms of depression and anxiety. Method: Outpatients with moderate to severe MDD were randomly assigned to receive paroxetine (n = 120) or placebo (n = 60). Results: Paroxetine significantly outperformed placebo on all psychological subscales of the syndrome measures, but not on any of the somatic subscales. The difference in score reduction between paroxetine and placebo was more than twice as great for the psychological symptoms compared to the somatic symptoms. Conclusions: Paroxetine appears to have a "true" pharmacological effect on the psychological but not on the somatic symptoms of depression and anxiety. Paroxetine's influence on somatic symptoms appears to be mostly duplicated by placebo.