The estrogen receptor alpha has been shown to be activated both in a ligand-dependent and in a ligand independent fashion. We investigated whether antidepressants may directly activate the estrogen receptor alpha or enhance ligand-dependent or ligand-independent activation of the estrogen receptor alpha. Whereas both ligand-dependent and ligand-independent activation of the estrogen receptor alpha could be demonstrated in transient transfection studies, antidepressants neither directly activated the estrogen receptor alpha nor did they enhance ligand-dependent or ligand-independent activation. Thus, there are differences between the glucocorticoid receptor and the estrogen receptor alpha with regard to ligand-independent activation and action of antidepressants.