There is considerable evidence that major depressive episode (MDE) in general, and treatment-resistant depression (TRD) in particular, may be accompanied by an immune-inflammatory response, as demonstrated by: an acute phase response (APR); an increased production of cytokines such as IL-6; and, activation of lymphocytes (T cells). Many studies have demonstrated an excessive hypothalamic-pituitary axis (HPA) activity in TRD. The APR seen in MDE is often accompanied by reduced levels of total serum protein (TSP) and changes in electrophoretically separated serum protein fractions. Acute phase proteins (APPs) migrate electrophoretically between albumin and γ-globulin fractions. The presence of APPs suggests that 5HT system disregulation may be related to the APR and to autoimmune pathogenesis in some MDE patients. The induction of anti-5HT and antiganglioside antibodies has been found to occur with viral infections and in response to stress and the production of cytokines.