Conference of Biological Psychiatry

«Stress and Behavior»

Proceedings of the 9th International Multidisciplinary Conference «Stress and behavior» Saint-Petersburg, Russia, 16-19 May 2005 Editor: Allan V. Kalueff, PhD



S.A Ivanova, G.G. Simutkin, N.M. Rakitina Mental Health Research Institute, Tomsk, Russia

Psychological stress and depressive disorder are associated with several immune alterations, including reduced cell proliferation and natural killer cell activity and disturbances of cytokine levels (Miller, 1998, 2004). Programmed death of cells by apoptosis is regarded as a protective mechanism of organism against an accumulation and spread of defective cells. Apoptosis can be enhanced by a variety of external stimuli, such as stress, viral infections, medications and pathological conditions. This phenomenon can be mediated via various pathways that cause condensation of the cytoplasm and chromatin, nuclear fragmentation, and ultimate sequestration of cellular contents into membrane-bound apoptotic bodies. Stress may alter DNA repair mechanisms; for example, lymphocytes from psychiatric inpatients with higher levels of depressive symptoms demonstrated impairment in their ability to repair cellular DNA damaged by exposure to x-irradiation. Moreover, psychotropic (antidepressant) medications can be effect on various immune functions, including normal physiological programmed cell death of lymphocytes. The aim of this investigation was to study apoptosis of immunocompetent cells in patients with depression in the process of the antidepressant therapy.

Methods. The test group was comprised of 15 patients with depressive disorders. Extract herbae Hyperici (medicine Negrustin, «Hexal» company, Germany) was prescribed for the therapy of depressive disorder. The patients received 2 capsules (containing 1200 mkg of active substance hypericin) daily for three weeks. The inclusion criterion was depression of moderate and mild degree (diagnosed according to ICD10: F32-depressive episode; F33 — recurrent affective disorder; F340.1 — persistent affective disorder (dysthymia). The exclusion criteria were any other psychiatric disorder or any immunological disorder. The clinical efficiency and safety of the therapy was assessed in points representing the dynamics of depressive condition. The investigation was carried out in dynamics: before the beginning of the pharmacotherapy vs. the background of depressive symptoms and after the course of Negrustin. Also, we examined 20 mentally and somatically healthy persons matched in sex and age as controls for biological investigation. We counted number of leukocytes, percent CD95+lymphocytes and morphological changes characteristic of apoptosis in lymphocytes and neutrophiles. Percent CD95+lymphocytes (lymphocytes with expression FAS-receptors) was counted using fluorescent microscopy. We prepared smears from venous blood onto a glass slide and minimum of 200 cells were examined for morphological changes characteristic of apoptosis (nuclear condensation, vacuolation, and blebbing), with the use of light microscopy.

Results and discussion. In the course of studies we found that the clinical efficiency of the Negrustin therapy of the depressive syndrome in patient was comparable with traditional antidepressant agents. We observed significantly increased cells’ apoptosis of depressive patients as the percentage of lymphocytes with expression FAS-receptors, also as cells with morphological changes characteristic of apoptosis (nuclear condensation, vacuolization, and blebbing). The percentage of lymphocytes with expression

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FAS-receptors was 16.88 ± 1.42% vs. 12,00 ± 0.77% in controls, p < 0.05). The normalization of CD95+lymphocytes was observed after conducted treatment with Negrustin. Level of spontaneous apoptosis of neutrophils in smears in patients with depressive disorder before treatment reliably differed from values observed in healthy persons (0.89 ± 0.57% and 0.25 ± 0.12%, respectively, p < 0.05). After the treatment, number of neutrophils exposed to apoptosis significantly decreased up to 0.20 ± 0.10%. Also, we demonstrated a significant increase lymphocytes with fragmented nucleus in schizophrenic patients (2.89 ± 0.71% and 0.97 ± 0.35% in control, p < 0.05). After Negrustin therapy, a significant decrease of number of lymphocytes with signs of apoptosis has been detected (1.19 ± 0.43%). Our data show an increased apoptosis in peripheral blood cells of patients with depression compared with controls and these data may be attributable to the interactions of the central nervous system and the immune system. Increase of the programmed cell death may suggest a «suicidal» tendency of the immune system in depressed patients and could lead to a vulnerability of the immune system, with decreased ability to resist infections, tumors, or autoimmune diseases (Mendelovic et al., 1999). Eilat et al. (1999) hypothesized that depressive patients can exploit their immune system for suicide, and one of the possible mechanisms includes apoptosis. Our data show that antidepressant therapy may have potent immunomodulatory properties, reducing the expression of receptors to Fas-dependent death, and altering apoptosis of immunocompetent cells.

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