A critical appraisal of mitogen-induced lymphocyte proliferation in depressed patients. OBJECTIVE: The authors' goal was to evaluate the utility of mitogen-induced lymphocyte proliferation assays in clinical research in psychoimmunology. METHOD: They examined 23 depressed patients and 23 matched comparison subjects with this assay. There were no significant differences between these groups. They then combined the results of this study with the results of their previous study of 20 depressed patients and 20 comparison subjects to examine possible determinants of lymphocyte proliferation in depression. RESULTS: Depressed patients with lower proliferative responses than their matched comparison subjects had lower depression subscale, anergia subscale, and total scores on the Brief Psychiatric Rating Scale than did patients with higher proliferative responses than their matched comparison subjects. This finding was unexpected and unexplained. Depressed patients with lower proliferative responses than their matched comparison subjects also had fewer obsessions and compulsions and less psychomotor agitation according to the Schedule for Affective Disorders and Schizophrenia interview than did patients with higher proliferative responses than their matched comparison subjects. Stepwise discriminant analysis and cluster analysis contributed little further understanding of the determinants of in vitro lymphocyte proliferation of cells from depressed patients. CONCLUSIONS: Longitudinal studies using multiple serial determinations of mitogen-induced lymphocyte proliferation are the minimal design needed to make this assay useful in further evaluating any immune system changes in depression. 