Pergamon zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Psychoneuroendocrinology, Vol. 20, No. 2. pp. 11 I-1 16. 1995 Copyright 0 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0306-4530/95 $9.50 + .OO 0306-4530(94)ooo66-2 INVITED EDITORIAL zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQP THE MONOCYTE-T-LYMPHOCYTE HYPOTHESIS OF MAJOR DEPRESSION MICHAEL MAES,’ RONALD SMITH,~ and SIMON SCHARPE~ ‘Department of Psychiatry, University Hospitals of Cleveland, Cleveland, Ohio, 44106. USA and Department of Psychiatry, University Hospital of Antwerp, Edegem 2650, Belgium; ?Siera Pacific Seminars, Modesto, California USA; and 3Department of Medical Biochemistry, University of Antwerp (WA), Belgium zyxwvutsrqponmlkjihgfedcbaZYXWVUT (Received 16 May 1994) A SUBSTANTIAL AMOUNT of research concerned with immunity in relation to major depression has been carried out over the last decade. The results were often interpreted to indicate that major depression is accompanied by immunosuppression, as suggested by blunted ex vivo mitogen-induced lymphoproliferative responses and natural killer cell activity (NKCA). Accordingly, the first immune studies carried out by our laboratories (around 1986) were conducted to examine the immunosuppression hypothesis through, for example, flow cytometric measurements of peripheral blood mononuclear cells (PBMC), functional immune tests, and the assays of monocytic and lymphocytic products, such as cytokines. Unexpectedly, the initial results showed a panel of signs indicative of immune activation (e.g., Maes et al., 1991, 1992). Moreover, a subsequent review of previous studies revealed evidence of immune activation in major depression, although the results were never interpreted as such. Smith formulated the macrophage hypothesis of major depression in 1991 and suggested that our results together with those of previous studies corroborated the hypothesis that activation of peripheral blood monocytes and T lymphocytes play a role in the pathophysiology (or even pathogenesis) of that illness (Smith, 1991). The evidence for the role of activation of peripheral blood monocytes and T lympho- cytes in the pathophysiology (or pathogenesis) of major depression involves consideration of: (a) increased production of monocytic or T- lymphocytic products, such as cytokines; signs of T-cell activation; and any immune-inflammatory alterations which may be related to activation of monocytes-T lymphocytes; (b) possible effects of peripheral blood mono- cytes-T lymphocytes or their products on brain structures that may be involved in the pathogenesis of major depression; (c) the possible involvement of monocytes-T lymphocytes or their products in the neuroendocrine or monoaminergic pathophysiology of major depression; (d) a theoretical explanation which relates the observed signs of Address correspondence and reprint requests to: Michael Maes, MD, PhD, Department of Psychia- try, AZ Stuivenberg, Lange Beeldekensstraat 267, 2060 Antwerp, Belgium. 111