Systemic immunization with altered myelin basic protein peptide produces sustained antidepressant-like effects.

Immune dysregulation, specifically of inflammatory processes, has been linked to behavioral symptoms of depression in both human and rodent studies. Here, we evaluated the antidepressant effects of immunization with altered peptide ligands of myelin basic protein (MBP)-MBP87-99[A91, A96], MBP87-99[A91], and MBP87-99[R91, A96]-in different models of depression and examined the mechanism by which these peptides protect against stress-induced depression. We found that a single dose of subcutaneously administered MBP87-99[A91, A96] produced antidepressant-like effects by decreasing immobility in the forced swim test and by reducing the escape latency and escape failures in the learned helplessness paradigm. Moreover, immunization with MBP87-99[A91, A96] prevented and reversed depressive-like and anxiety-like behaviors that were induced by chronic unpredictable stress (CUS). However, MBP87-99[R91, A96] tended to aggravate CUS-induced anxiety-like behavior. Chronic stress increased the production of peripheral and central proinflammatory cytokines and induced the activation of microglia in the prelimbic cortex (PrL), which was blocked by MBP87-99[A91, A96]. Immunization with MBP-derived altered peptide ligands also rescued chronic stress-induced deficits in p11, phosphorylated cyclic adenosine monophosphate response element binding protein, and brain-derived neurotrophic factor expression. Moreover, microinjections of recombinant proinflammatory cytokines and the knockdown of p11 in the PrL blunted the antidepressant-like behavioral response to MBP87-99[A91, A96]. Altogether, these findings indicate that immunization with altered MBP peptide produces prolonged antidepressant-like effects in rats, and the behavioral response is mediated by inflammatory factors (particularly interleukin-6), and p11 signaling in the PrL. Immune-neural interactions may impact central nervous system function and alter an individual's response to stress.

The immunomodulatory effect of ketamine in depression.

Major depression is one of the most frequent psychiatric conditions. Despite many available treatment methods, more than 30% of patients do not achieve remission, even after trying several antidepressants and augmentation strategies. S-enantiomer of ketamine, well-known anesthetic and analgesic, has been recently approved by Food and Drug Administration in the intranasal form as a new generation antidepressant. However, the mechanism in which ketamine reduces depressive symptoms in treatment-resistant depression patients is still not completely understood. There are several theories explaining how ketamine might reduce depressive symptoms, which have been described in detail; one of them is immunomodulatory effect of ketamine, according to the inflammatory theory of depression. In the review authors present and summarize studies showing ketamine effect on human immune system ex vivo and in vitro, including changes in cytokine levels, number, ratio and activity of various immune cell population and the correlation with clinical improvement in depressive symptoms. Most of the results confirm the anti-inflammatory effect of ketamine. There are only a few studies in the population of patients suffering from depression receiving ketamine, focused on correlation between immunological changes and clinical outcome of the therapy; further studies of that area are neccesary for understanding the immunomodulatory effect of ketamine in depression.

Natural Killer Cells may Exert Antidepressant-like Effects in Mice by Controlling the Release of Inflammatory Factors.

Depression or stress is reportedly related to the overflow of inflammatory factors in the body and T cells were reported to play important roles in balancing the release of inflammatory factors through vagus nerve circuit. However, few works have been conducted to find if natural killer (NK) cells can also exert the similar function in the reported vagus nerve circuit as T cells and if there was any relationship between depression and this function. In the present study, the behavioral tests on BALB/c mice indicated that the depressant-like symptoms could be improved and simultaneously the concentrations of inflammatory factors in peripheral blood could be reduced significantly by adoptively transferring NK cells into stressed BALB/c mice. The results revealed that NK cells could control the release of inflammatory factors secreted by macrophages and ß2-AR (ß2-adrenergic receptor) on the NK cells were of great importance. Behavioral tests on NCG mice indicated that the antidepressant-like effects of NK cells notably declined after adoptively transferring NK cells with ß2-AR deficiency or with ChAT (choline acetyltransferase) deficiency into stressed NCG mice. Simultaneously, the anti-inflammatory effects also declined significantly both in vivo and in vitro, which indicated that the antidepressant-like property of NK cells may be related to its ability of controlling the release of inflammatory factors. Taken together, we find that NK cells may balance the release of inflammatory factors in our body by transporting the information between the terminal vagal branches and macrophages, which is the mechanism that NK cells may exert antidepressant-like effects.

Blockade of interleukin-6 receptor in the periphery promotes rapid and sustained antidepressant actions: a possible role of gut-microbiota-brain axis.

Depression is a common, severe and chronic psychiatric disease. Although the currently available antidepressants have been used in the treatment of depression, their beneficial effects are limited. Accumulating evidence suggests that pro-inflammatory cytokines such as interleukin-6 (IL-6) have an important role in the pathogenesis of depression. This study was undertaken to examine whether anti-mouse IL-6 receptor antibody (MR16-1) induces antidepressant effects in a social defeat stress model. Intravenous injection of MR16-1 induced rapid-onset and long-lasting antidepressant effects in susceptible mice after social defeat stress through its anti-inflammatory actions. In contrast, intracerebroventricular injection of MR16-1 induced no antidepressant effects in susceptible mice. Furthermore, treatment with MR16-1 could significantly normalize alterations in the expression of synaptic proteins (postsynaptic density protein 95 and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 1) and dendritic spine density in the brain regions of susceptible mice. Gut microbiota analysis using 16S ribosomal RNA gene sequencing showed that MR16-1 significantly improved decreased Firmicutes/Bacteroidetes ratio in susceptible mice. It also significantly improved decreased levels of Oscillospira in susceptible mice. These findings suggest that peripheral IL-6 has a key role in the pathogenesis of depression and that the blockade of IL-6 receptor in the periphery might have rapid-onset and long-lasting antidepressant effects by normalizing the altered composition of gut microbiota in susceptible mice after social defeat stress. Therefore, the blockade of IL-6 receptor in the periphery shows promise as a novel therapeutic approach for depressed patients with higher IL-6 blood levels.

Antidepressants: influence on cancer and immunity?

Two decades ago, it was hypothesized that antidepressants could alter the course of neoplastic diseases. However, contradictory findings indicated that antidepressants could either have carcinogenic properties or improve the disease outcome. Intriguingly, controversial results were reported on the action of antidepressant drugs on immune function. Further hypotheses proposed that antidepressants could indirectly affect the cancer prognosis through the modulation of antitumor activity. Here we review the literature in order to elucidate the influence of antidepressants on cancer and immunity.

Crosstalk between contact hypersensitivity reaction and antidepressant drugs.

Allergic contact dermatitis is a delayed-type hypersensitivity reaction mediated by hapten-specific T cells. Many cell types, inflammatory mediators and cytokines are involved in this reaction. Contact hypersensitivity is a self-limited reaction and can be regulated at different levels. Because it is known that disturbances in the immune system underpin the onset of depression and that antidepressant drugs have immunomodulatory effects, it can be hypothesized that antidepressants may have some efficacy in the treatment of contact hypersensitivity. There are some reports on the effectiveness of antidepressants in the inhibition of cutaneous sensitization in mice, and the aim of this narrative review is to assess the evidence for the effectiveness of antidepressant drugs in reducing the recurrence of contact hypersensitivity reactions.

Selective serotonin reuptake inhibitors inhibit human osteoclast and osteoblast formation and function.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants and one of the most commonly used medications. There is growing concern that SSRIs, which sequester in bone marrow at higher concentrations than brain or blood, increase bone fragility and fracture risk. However, their mechanism of action on human osteoclasts (OC) and osteoblasts (OB) differentiation remains unclear. METHODS: Expression of serotonin receptors (5-HTR), transporter (5-HTT), and tryptophan hydroxylase 1 (TPH1) was assessed in human OC (precursors and mature) and OB (nonmineralizing and mineralizing) by polymerase chain reaction. OC formation and resorption was measured in the presence of 5 SSRIs. OBs cultured with SSRIs for 28 days were assessed for alkaline phosphatase (ALP) and bone mineralization. Cell viability and apoptosis were determined by annexin V flow cytometry. RESULTS: OCs and OB expressed TPH1, 5-HTT, and 5-HTR1B. The 5-HTR2A was expressed only in OB, whereas 5-HTR2B expression increased from precursor to mature OC. All SSRIs (except citalopram) dose-dependently inhibited OC formation and resorption between 1 µmol/L and 10 µmol/L; order of potency: sertraline > fluoxetine > paroxetine > fluvoxamine > citalopram. Similarly, SSRIs (except citalopram) inhibited ALP and bone mineralization by OB but only at 30 µmol/L. Apoptosis was induced by SSRIs in OC and OB in an identical pattern to inhibitory effects. Serotonin treatment had no effect on either OC or OB parameters. CONCLUSIONS: These data demonstrate that SSRIs differentially inhibit bone cell function via apoptosis. This may explain the mechanisms of bone loss with chronic use and aid clinical choices.

Preparation of a polyclonal antibody against hypericin synthase and localization of the enzyme in red-pigmented Hypericum perforatum L. plantlets.

Hypericum perforatum is well known for its antidepressant and anti-inflammatory activities, for which hypericin and its derivatives are indicated to be the most active compounds. Hypericin synthase (Hyp-1) is the only protein proven to catalyze the synthesis of hypericin. In this study, the full-length cDNA of Hyp-1 was chemically synthesized according to the Hyp-1 sequence in GenBank (accession no. AY148090) and then cloned into the plasmid pET22b. Hyp-1 was expressed in Escherichia coli BL21 (DE3) and purified with a Ni-NTA column. The purified protein was used to immunize New Zealand white rabbits, from which an antiserum was purified by protein G affinity chromatography. The polyclonal antibody against Hyp-1 provides a valuable tool for the study of hypericin biosynthesis in H. perforatum. Expression of Hyp-1 and the cellular distribution of hypericin were analyzed in different organs of red-pigmented H. perforatum plantlets. The black glands were not the only site of hypericin accumulation and the results indicated that hypericin might be synthesized in mesophyll cells or in tissues of the root and/or stem and then transported to the glands. This work provides a foundation for further investigation of the regulatory mechanism of hypericin synthesis during the development of H. perforatum.

Pro-inflammatory cytokines are elevated in adolescent females with emotional disorders not treated with SSRIs.

BACKGROUND: Adults with major depressive disorder (MDD) show elevated levels of IL-6 and TNF-alpha. Studies of adolescents with MDD or anxiety disorders (AD) are few and present conflicting results. METHODS: We studied plasma cytokines in a clinical sample of adolescent females with MDD and/or clinical AD (n=60, mean age 16.8 years), compared to healthy controls (n=44; mean age 16.5 years). RESULTS: The clinical sample showed significantly higher values of IL-2 (Z=-4.09, p>0.0001), IL1-beta (Z=-2.40, p<0.05) and IL-10 (Z=-2.38, p<0.05) as compared to controls. The subgroup of the clinical sample not treated with SSRIs had a significant difference of IL-6 (Z=-2.26, p<0.05) in addition to the difference of IL-2 and IL1-beta, but showed no difference of IL-10 as compared to the controls. SSRI treatment was related to IL-6, explaining 26% of the variance in the clinical sample after controlling for BMI and symptom severity. In the clinical sample, levels of IL-6 and IFN-gamma were positively correlated with self-assessed symptoms of anxiety and/or depression (corr.coeff 0.35 resp 0.40 at p<0.05). LIMITATIONS: The cross-sectional design does not allow for conclusions on causality. The sample sizes were relatively small and a large drop-out in the clinical sample may have influenced the representativity. DISCUSSION: The study suggests that pro-inflammatory cytokines are part of the pathophysiology of emotional disorders in adolescent females and that SSRIs have anti-inflammatory properties. The findings prompt further studies on the specific mechanisms involved and may contribute to the development of more effective treatment and prevention.

Major depressive disorder and immunity to varicella-zoster virus in the elderly.

Major depressive disorder has been associated with activation of inflammatory processes as well as with reductions in innate, adaptive and non-specific immune responses. The objective of this study was to evaluate the association between major depression and a disease-relevant immunologic response, namely varicella-zoster virus (VZV)-specific immunity, in elderly adults. A cross-sectional cohort study was conducted in 104 elderly community dwelling adults ≥ 60years of age who were enrolled in the depression substudy of the shingles prevention study, a double blind, placebo-controlled vaccine efficacy trial. Fifty-two subjects had a current major depressive disorder, and 52 age- and sex-matched controls had no history of depression or any mental illness. VZV-specific cell-mediated immunity (VZV-CMI) was measured by VZV responder cell frequency (VZV-RCF) and interferon-γ enzyme-linked immunospot (ELISPOT) assays, and antibody to VZV was measured by an enzyme-linked immunosorbent assay against affinity-purified VZV glycoproteins (gpELISA). VZV-CMI, measured by VZV-RCF, was significantly lower in the depressed group than in the controls (p<0.001), and VZV-RCF was inversely correlated with the severity of depressive symptoms in the depressed patients. In addition, an age-related reduction in VZV-RCF was observed in the depressed patients, but not in the controls. Furthermore, there was a trend for depressive symptom severity to be associated with lower ELISPOT counts. Finally, VZV-RCF was higher in depressed patients treated with antidepressant medications as compared to untreated depressed patients. Since lower levels of VZV-RCF appear to explain the increased risk and severity of herpes zoster observed in older adults, these findings suggest that, in addition to increasing age, depression may increase the risk and severity of herpes zoster.

The effects of antidepressants on the results of skin prick tests used in the diagnosis of allergic diseases.

BACKGROUND: Some drugs may cause false negative results by suppressing the reactivity of the skin prick tests (SPTs). The aim of this survey was to show whether escitalopram, fluoxetine and sertraline had any effect on the reactivity of SPT. METHODS: Twenty-four patients who were admitted to the outpatient clinic of the Psychiatry Department at the Hacettepe University Hospital and planned to be treated by these antidepressants were included in the study between May and October 2008. SPTs with positive control (histamine), negative control and 3 common aeroallergens were performed in the beginning, at the first and fourth weeks. A questionnaire including 26 questions about respiratory symptoms and allergic diseases was filled in face to face by the fellow-in-training. The Visual Analog Scale (VAS) of current respiratory and nasal symptoms was recorded at all 3 visits. RESULTS: There were no statistically significant differences between the 3 mean diameters measured at 3 time points in addition to the mean diameters of the wheals between groups using escitalopram, sertraline and fluoxetine (p > 0.05). There was a statistically significant decrease between the VAS of nasal symptoms at the 3 visits (p < 0.05). CONCLUSIONS: Escitalopram, fluoxetine and sertraline do not seem to affect the reactivity of SPTs. Nasal symptoms might have been decreased due to both the allergic treatment suggested and the end of the pollen season.

Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression.

The first findings that depression is characterized by cell-mediated immune activation and inflammation were published between 1990-1993 (Maes et al.). Recently, it was reported that--based on meta-analysis results--depression is an inflammatory disorder because the plasma levels of two cytokines are increased, i.e. interleukin-(IL)-6 and tumor necrosis factor-α (TNFα). The same meta-analysis found that plasma IL-2 and interferon-(IFN)γ levels are not altered in depression, suggesting that there is no T cell activation in that illness. The present paper reviews the body of evidence that depression is accompanied by cell-mediated immune activation. The findings include: increased serum levels of the soluble IL-2 receptor (sIL-2R) and the sCD8 molecule; increased numbers and percentages of T cells bearing T cell activation markers, such as CD2+CD25+, CD3+CD25+, and HLA-DR+; increased stimulated production of IFNγ; higher neopterin and sTNFR-1 or sTNFR-2 levels; induction of indoleamine 2,3-dioxygenase (IDO) with lowered levels of plasma tryptophan and increased levels of tryptophan catabolites along the IDO pathway (TRYCATs); and glucocorticoid resistance in immune cells. Interferon-α (IFNα)-based immunotherapy shows that baseline and IFNα-induced activation of T cells, IDO activity and TRYCAT formation are related to the development of IFNα-induced depressive symptoms. Animal models of depression show that a cell-mediated immune response is related to the development of depression-like behavior. Antidepressants and mood stabilizers suppress different aspects of cell-mediated immunity and rather specifically target IFNγ production. This review shows that inflammation and cell-mediated immune activation are key factors in depression.

Antidepressant drugs in oral fluid using liquid chromatography-tandem mass spectrometry.

An analytical procedure for the determination of widely prescribed drugs for the treatment of depression and anxiety disorders, including amitriptyline, cyclobenzaprine, imipramine, dothiepin, doxepin, fluoxetine, sertraline, trimipramine, protriptyline, chlorpromazine, clomipramine, and some of their metabolites (nortriptyline, desmethyldoxepin, desipramine, desmethyltrimipramine, norclomipramine) in oral fluid has been developed and validated using liquid chromatography with tandem mass spectral detection. The oral fluid samples were collected using the Quantisal device and screened with enzyme-linked immunosorbent assay. Any drugs present were quantified using mixed-mode solid-phase extraction followed by mass spectrometric detection in positive electrospray ionization mode. For confirmation, two transitions were monitored, and the ratio between the two was required to be within 20% of the known calibration standard. Because of the worldwide shortage of acetonitrile, which was first reported in October 2008, the mobile phase was optimized to use methanol as the organic component. For all compounds, the lower limit of quantitation was 5 ng/mL; the intraday precision ranged from 2.9 to 8.2% (n = 6); interday precision from 1.5 to 6.2% (n = 30) at a concentration of 40 ng/mL. The percentage recovery of antidepressants from the oral fluid collection pad was calculated at a concentration of 40 ng/mL and ranged from 51.4 to 84.1% (n = 6). The aim of the study was to develop a confirmatory procedure for drugs in oral fluid that had been identified as presumptively positive for antidepressants and related compounds. The methods were applied to research oral fluid specimens received into our facility for testing.

Genetic catalepsy and ultralow dose antibodies to S-100B antigen.

We studied consumption of 20% sucrose solution by rats genetically predisposed to catalepsy (GC strain) during training. The consumption of sucrose solution by GC rats was lower in comparison to that in Wistar rats. "Potentiated" antibodies to S-100B antigen administered orally after training sessions increased the number and duration of subsequent contacts of rats with sucrose solution.

Lithium and antidepressants: stimulating immune function and preventing and reversing infection.

The ability to safely and economically stimulate immune function would transform the humanitarian and economic landscapes of nosocomial, surgical and antibiotic-resistant infections, as well as reduce the burden of epidemics, pandemics and bioterrorism. Such stimulation is widely held to be beyond our reach, an unfortunate misconception. As early as the mid 1980s sufficient evidence had accumulated to be able to state with conviction that lithium and antidepressants have these properties. Excessive production of prostaglandin E2 activates microorganisms and suppresses immune function, and lithium and antidepressants oppose prostaglandin E2. Immunostimulation is non-specific, possibly relevant to all infections, pertinent to one, two, or more concurrent infections, and highly cost/effective. In controlled studies an antidepressant would be relevant to that agent and only that agent, rendering such studies worthless. Over the past twenty years 22 drug companies have declined interest in developing antidepressants as antiinfectives. It would be unethical to deny the infected these well documented benefits.

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.

Antidepressant properties of antibodies to serotonin, brain-specific S100 protein, and delta sleep-inducing peptide.

Potentiated antibodies to delta sleep-inducing peptide and S100 protein produced an antidepressant effect in Wistar rats. This effect was more pronounced after combined treatment with these antibodies. It can be assumed that these antibodies modulate neurobiological mechanisms of positive emotional reinforcement and, therefore, affect the resistance to depression associated with psychoemotional stress.

Comparative efficiency of Proproten-100 during the therapy of patients with alcoholism in the stage of therapeutic remission.

An open comparative clinical study evaluated the efficiency of Proproten-100 in reliving affective, somatovegetative, behavioral, and cognitive post-withdrawal disorders and manifestations of primary pathological alcohol addiction in patients with alcohol dependence in the stage of therapeutic remission. We compared the efficiency of Proproten-100 and standard symptomatic drugs. The preparation possessed anxiolytic, antidepressant, and vegetostabilizing properties, produced a moderate soporific effect, and had no sedative activity in patients with dysphoric depressions and psychopathic disorders. Proproten-100 was more effective during the therapy of patients with anxious and wistful depressions. Proproten-100 increased the contents of IgG and natural antibodies against S100 protein in the blood from patients. The preparation did not cause side effect or development of tolerance. Proproten-100 has psychotropic properties and holds much promise for long-term treatment of patients with alcohol dependence to reduce the incidence of recurrences.