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To investigate the possible differential sensitivity of hydrocortisone (HCO) on immunoglobulin (Ig) production in depression in relation to endogenous cortisol levels, blood was obtained at 8 am and 4 pm from 10 inpatients with major depression according to DSM-III-R criteria and 10 age- and sex-matched healthy subjects. Peripheral blood lymphocytes were cultured in the presence of graded concentrations (10-9-10-5M) of HCO to study the effect on immunoglobulin (IgG and IgM) synthesis. In addition, peripheral blood lymphocytes were cultured in the presence of pokeweed mitogen (PWM) to study any additional effect of graded concentrations of HCO (10-9-10-5M) on IgG and IgM synthesis. Mean plasma cortisol levels at both time points were higher in patients compared to controls. HCO-preferentially at concentrations of 10-8-10-6 molar-stimulated IgG and IgM production in controls, except for IgM production in the 8 am samples, when the cells were cultured in the absence of PWM. Under these culture conditions, HCO stimulated IgG but not IgM synthesis in depressed patients. PWM-driven IgG and IgM synthesis in controls was stimulated by HCO in both the 8 am and the 4 pm samples. In patients PWM driven IgG synthesis was stimulated by HCO in the 8 am but not in the 4 pm samples. PWM-stimulated IgM synthesis was not augmented by HCO in depressed patients. We conclude that a differential sensitivity to the effects of HCO exists in in vitro IgG and IgM synthesis between depressed patients and controls. Furthermore, we suggest that immunocompetent cells of depressed patients possess corticosteroid-resistant properties.