It has been proposed that the reason antidepressants outperform placebo in clinical trials is because patients experience side effects that inform them they have been given the active drug.
In a study in Molecular Psychiatry (25 July 2017), researchers analysed data on 15 randomised control trials involving more than 3,000 patients with major depressive disorder who were assigned to citalopram, paroxetine or placebo
They found that the reduction in depressed mood at six weeks of treatment was significantly greater among patients assigned to either drug versus placebo. And they showed that this was true for patients who both did and did not experience early adverse events.
The findings show that the pharmacodynamics properties of citalopram and paroxetine are clearly superior to placebo, contradicting the theory that antidepressants outperform placebo solely because of their side effects, the team concluded.
 Hieronymus F, Lisinski A, Nilsson S et al. Efficacy of selective serotonin reuptake inhibitors in the absence of side effects: a mega-analysis of citalopram and paroxetine in adult depression. Mol Psych 2017; 00, 1–6. doi: 10.1038/mp.2017.147