The immunostimulating and antimicrobial properties of lithium and antidepressants.

Eicosanoids are products of arachidonic acid (AA), an essential fatty acid. They include prostaglandins (PGs), prostacyclin (PGI2), thromboxanes (TXs), leukotrienes (LTs) and hydroxy fatty acids. AA is derived enzymatically from membrane phospholipids and to a lesser extent the diet. Eicosanoids self-regulate every cell, including those synthesizing serotonin, norepinephrine and dopamine and those subserving immune function, such as T-cells, B-cells, natural killer cells, macrophages, monocytes and dendritic cells. There is objective evidence that prostaglandins regulate the physiology of the hypothalamic-pituitary-adrenal axis (HPA). Elucidation of the structure and metabolic pathways of eicosanoids galvanized researchers into illuminating their role in physiology, pathology and pharmacology. Striking contradictions arose: eicosanoids were shown to activate and suppress microorganisms, potentiate and suppress immunity and possess pro- and anticancer properties. As prostaglandins are the most heavily studied eicosanoids in the context of mood and immunity I will focus on them in this article. I will present evidence of the immunostimulating and antimicrobial properties of lithium and antidepressants and propose that these properties are linked to the antiprostaglandin actions of these compounds.

The effect of lithium administration in animal models of depression: a short review.

The aim of this short review was to collate the data involving the effects of lithium alone, or in combination, with antidepressant drugs in several animal models of depression. It has been shown that lithium administration reduced immobility in the mouse forced swimming test when given 30 min, but not 45 min, before testing. Further studies indicated that this activity was probably a result of an activity on serotonin (5-HT) 1A and 1B receptor subtypes. Lithium treatment has been shown to reverse helpless behaviour in the learned helplessness model of depression after chronic treatment (30 days), where lithium was administered in the drinking water. Further studies showed that acute (5 days) administration of lithium failed to reverse behavioural deficits. In the olfactory bulbectomised rat model of depression, several immunological and enzymatic functions have been shown to be altered and these changes are regularised by antidepressant treatment as well as lithium administration for 15 days. Hypokinesia (reduced locomotor activity) is a phenomenon observed following immobilisation stress in rats. This behavioural deficit was attenuated by lithium together with a wide range of antidepressant drugs used in the treatment of unipolar depression at non-stimulant doses. In addition, a single administration of lithium slightly inhibited midbrain raphe lesion-induced muricidal behaviour (25%); however, repeated treatment (5 days) significantly attenuated this behavioural deficit. Lithium treatment has also been shown to reverse behavioural and biochemical deficits induced by reserpine together with those induced by acute administration of single intracerebroventricular (i.c.v.) dose of the Na, K-ATPase-inhibiting compound, ouabain. Long-term studies of lithium augmentation have not been performed, so that no clear recommendations for the duration of this therapy can be made. The points raised in this short review endorse the commencement of such studies.

Comparison of adjuvants with respect to serum IgG antibody response in orally immunized chickens.

We have previously shown that oral immunization with non-replicating antigens hardly induced serum IgG antibody response in chickens and addition of sodium fluoride (NaF) to the immunogen markedly improved their immunological states. In the present study, taurine, lithium and Quillaja saponin (Q-SAP) were compared with NaF with respect to their enhancement of serum IgG antibody response in chickens after oral immunization. The antibody titer of chickens which received Q-SAP as the mucosal adjuvant tended to be higher than that of chickens which received antigen plus NaF. Simultaneous administration of antigen with lithium or taurine elicited a higher antibody titer in chickens compared to those of chickens orally immunized with antigen alone, but the effect of these two adjuvants was less efficient compared with that of NaF. These results suggested that Q-SAP as well as NaF is useful as an oral adjuvant for chickens.

Prevalence of antithyroid antibodies in mood disorders.

We examined the prevalence of antimicrosomal and antithyroglobulin antibodies in psychiatric inpatients with unipolar depression (N = 218), bipolar disorder manic (N = 51), bipolar disorder depressed (N = 19), and bipolar disorder mixed (N = 26) in comparison with two control groups: psychiatric inpatients with adjustment disorder (N = 80) and family medicine outpatients without current psychiatric illness (N = 144). A statistical analysis that controlled for age and sex revealed the frequency of positive antibody titers not to be increased in patients with a diagnosis of unipolar depression (6.9%) or bipolar disorder manic (3.9%), when compared with patients with adjustment disorder (2.5%) and non-psychiatric subjects (6.9%). There was a weak trend toward an increased prevalence of antithyroid antibodies in patients with bipolar disorder, mixed (19%) or depressed subtype (16%). The excess occurrence of antibodies in patients with either mixed or depressed bipolar disorder did not appear to be related to lithium exposure, which was similar in all bipolar subgroups. When the intervening influences of age and sex are taken into account, unipolar depression does not appear to be associated with an excessive rate of antithyroid antibodies; however thyroid autoimmunity may be weakly associated with subtypes of bipolar disorder in which depressive symptoms are prominent.

Stress, depression and schizophrenia in view of psychoimmunology.

The authors discuss the influence of stress on the immunological system. They describe changes in this system in depressive and in schizophrenic patients and analyze the eventual effect of these changes in the pathogenesis of endogenous psychopathology. The authors conclude that despite the fact that research into the immunology of these aspects are in the beginning stages, the data so far collected indicate a promising result.

The neuro-immune network. Some recent developments.

Neuroimmunomodulation encompasses, by definition, numerous components and activities primarily derived from the immune system, and treats the immunoneuroendocrine interconnections at different levels of the integrated whole functioning organism. The arbitrary unit of the immunoneuroendocrine network is the immune microenvironment composed of lymphocytes, neurons, endocrine cells, nonlymphoid accessory cells, humoral factors from immune, nervous, endocrine and other tissues, receptors for endogenous and exogenous ligands, pathways for transduction of biological signals, physiological ions, various magnetic and electromagnetic compartments, and impulses from the higher nervous activity (the mind, the psyche). The neuroimmunomodulation is a marvelous mechanism from which arises an amazing quantity of variables and intercommunications in the living organism. Being a multidisciplinary science par excellence, neuroimmunomodulation is strongly antidogmatic and favors multidirectional organization of research. That means that actions of the immune, nervous and endocrine systems should be studied together in terms of intercommunications among identifiable structures and processes. Therefore, research endeavors in neuroimmunomodulation have different directions with seminal discoveries much too numerous to list here. This mini-review is confined to some recent findings dealing with the immunomodulatory activity of micromagnetic fields when applied to the brain, the humoral and cell-mediated components of certain neurological and psychiatric diseases, the autoimmune features in heroin addicts in relation to dementia and HIV infection, the neuroimmunobiology of lithium cation, and the in vivo immune function of enkephalins, and methionine-enkephalin in particular.

Enhancing effects of oral adjuvants on anti-HBs responses induced by hepatitis B vaccine.

Hepatitis B (HB) vaccine is very promising for the prevention of HB infection. There exist, however, some non-responders to current vaccination trials. In this study, taurine, parotin and lithium were selected as adjuvants which can be administered orally. The mechanisms of these three materials as adjuvants and their effects on HB vaccine were investigated in mice. For instance, taurine induced polyclonal antibody production and exhibited adjuvant activity. Although taurine did not have any activity on the proliferation of thymocytes nor stimulate IL-2 production, taurine did induce IL-1 production by macrophages. It was considered that taurine-induced IL-1 would play an essential role in the proliferation and differentiation of B cells. Parotin also induced polyclonal antibody production and exhibited adjuvant activity. These effects of parotin were not affected even if macrophages or T cells were depleted, and parotin itself had an IL-1-like activity. Therefore, it was considered that parotin acted directly on B cells by its IL-1-like activity and mitogenic activity, resulting in the proliferation and differentiation of B cells. Lithium induced neither polyclonal antibody production, nor IL-1 or IL-2 production. However, when given with an antigen, lithium activated the humoral immune system, resulting in the augmentation of antibody production. Oral administration of taurine, parotin and lithium were capable of restoring antibody responses to HB surface antigen (HBsAg) in HBsAg-nonresponder mice. Furthermore, taurine, parotin and lithium enhanced the adjuvant effects of aluminium contained in the present HB vaccine. These observations indicate that use of these oral adjuvants may open new perspectives in the field of human HB vaccination.

Immunoregulatory properties of some heavy metals in physiology and pathology conditions. Part I.

The paper presents literature review dealing with the role of some trace metals in immunological processes of the body. The author took into consideration iron, zinc, magnesium, selenium, lithium and vanadium. They take part in the control of immunity processes nonspecifically potentializing the immunological response of modifying it in the presence of mitogens and antigens. The place where this interaction probably undergoes are the membrane receptors of lymphocytes and macrophages for mito- and antigens. The trace metals seem to control and reproduce their activity, taking part in the transport through the membranes of immunologically competent cells.

The histopathologic features of lithium-associated thyroiditis.

The case of a 62-year-old woman with lithium-associated thyroiditis is presented. Lithium can produce goiters associated with hypothyroidism and, less commonly, hyperthyroidism and euthyroidism. The characteristic histopathologic features of the affected thyroid gland included fibrosis, lymphoid follicles with atrophy, and hyperplasia of thyroid follicles. The pathogenetic mechanism appears to be immunologic, with lithium acting as a haptene with a thyroid antigen to induce an "autoimmune" type of thyroiditis.

Lithium as an immunologic adjuvant.

Lithium, an adenylate cyclase inhibitor, stimulates a variety of in vitro indices of immune function, including proliferation of lymphocytes in response to mitogens, rosette formation by T-cells and phagocytosis by macrophages. Lithium enhances these immunologic responses at concentrations comparable to those achieved in patients receiving lithium for treatment of manic-depressive disorders. Lithium may prove to have important therapeutic applications as an immune adjuvant, particularly in immune deficiency states associated with excessive C-AMP production.