There is some evidence that major depression--in particular, treatment-resistant depression (TRD)--is accompanied by activation of the inflammatory response system and that proinflammatory cytokines may play a role in the etiology of depression. This study was carried out to examine the effects of antidepressive agents, i.e., imipramine, venlafaxine, L-5-hydroxytryptophan, and fluoxetine on the production of interferon-gamma (IFN-gamma), a proinflammatory cytokine, and interleukin-10 (IL-10), a negative immunoregulatory cytokine. Diluted whole blood of fluoxetine-treated patients with TRD (mean age, 50.6+/-3.9 years) and age-matched healthy controls (mean age, 51.6+/-1.7 years) and younger healthy volunteers (mean age, 35.4+/-9.6 years) was stimulated with phytohemagglutinin (1 microg/mL) and lipopolysaccharide (5 microg/mL) for 48 hours with and without incubation with the antidepressants at 10-6 M and 10(-5) M. IFN-gamma and IL-10 were quantified by means of enzyme-linked immunoassays. The ratio of IFN-gamma to IL-10 production by immunocytes was computed because this ratio is of critical importance in determining the capacity of immunocytes to activate or inhibit monocytic and T-lymphocytic functions. All four antidepressive drugs significantly increased the production of IL-10. Fluoxetine significantly decreased the production of IFN-gamma. All four antidepressants significantly reduced the IFN-gamma/IL-10 ratio. There were no significant differences in the antidepressant-induced changes in IFN-gamma or IL-10 between younger and older healthy volunteers and TRD patients. Tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-noradrenaline reuptake inhibitors, as well as the immediate precursor of serotonin, have a common, negative immunoregulatory effect by suppressing the IFN-gamma/IL-10 production ratio. It is suggested that the therapeutic efficacy of antidepressants may be related to their negative immunoregulatory effects.